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Cyanopeptide Co-Production Dynamics beyond Mirocystins and Effects of Growth Stages and Nutrient Availability

  • Regiane Natumi
    Regiane Natumi
    Department of Environmental Chemistry, Swiss Federal Institute of Aquatic Science and Technology (Eawag), 8600 Dübendorf, Switzerland
    More by Regiane Natumi
  •  and 
  • Elisabeth M.-L. Janssen*
    Elisabeth M.-L. Janssen
    Department of Environmental Chemistry, Swiss Federal Institute of Aquatic Science and Technology (Eawag), 8600 Dübendorf, Switzerland
    *Email: [email protected]. Phone: +41 58 765 5802.
    More by Elisabeth M.-L. Janssen
    Orcidhttp://orcid.org/0000-0002-5475-6730
Cite this: Environ. Sci. Technol. 2020, 54, 10, 6063–6072
Publication Date (Web):April 17, 2020
https://doi.org/10.1021/acs.est.9b07334

Copyright © 2022 American Chemical Society. This publication is licensed under CC-BY-NC-ND.

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Abstract

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Intensified cyanobacterial bloom events are of increasing global concern because of adverse effects associated with the release of bioactive compounds, including toxic cyanopeptides. Cyanobacteria can produce a variety of cyanopeptides, yet our knowledge about their abundance and co-production remains limited. We applied a suspect-screening approach, including 700 structurally known cyanopeptides, and identified 11 cyanopeptides in Microcystis aeruginosa and 17 in Dolichospermum flos-aquae. Total cyanopeptide concentrations ranged from high nmol to μmol gdry–1 with slightly higher cell quotas in the mid-exponential growth phase. Relative cyanopeptide profiles were unchanged throughout the growth cycle. We demonstrate that quantification based on microcystin-LR equivalents can introduce an error of up to 6-fold and recommend a class-equivalent approach instead. In M. aeruginosa, rarely studied cyclamides dominated (>80%) over cyanopeptolins and microcystins. While all nutrient reductions caused less growth, only lowering phosphorous and micronutrients reduced cyanopeptide production by M. aeruginosa. Similar trends were observed for D. flos-aquae and only lowering nitrogen decreased cyanopeptide production while the relative abundance of individual cyanopeptides remained stable. The synchronized production of other cyanopeptides along with microcystins emphasizes the need to make them available as reference standards to encourage more studies on their occurrence in blooms, persistence, and potential toxicity.

Introduction

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Cyanobacterial blooms are a global challenge for freshwater ecosystems because they are detrimental to water quality. Bloom events can compromise recreational activities and are also considered a growing public health concern due to the production of toxins. (1,2) A global increase in frequency and intensity of cyanobacterial blooms is in part related to increasing nutrient input and changing climate conditions (e.g., longer-lasting warm temperature periods, changes in hydrological mixing, etc.). (3) This increase has prompted the interest of scientists and water managers to elucidate the factors controlling not only proliferation of cyanobacteria but also production of their bioactive metabolites that are potentially toxic.
Numerous studies have been conducted in the past decade regarding the occurrence of microcystins, one class of cyanopeptides that has been classified as hepatotoxic and has been linked to animal poisoning and even human fatalities. (4−7) Consequently, water quality guidelines have been included in risk management frameworks of the WHO focusing on microcystin-LR, the most frequently reported variant of more than 200 known microcystins. (8) However, besides the well-known class of microcystins, cyanobacteria produce a variety of cyanopeptides, which can be classified by structural similarities, including cyclamides, cyanopeptolins, aeruginosins, anabaenopeptins, and microginins. Over the past few decades, hundreds of cyanopeptides have been identified in pure cultures and biomass collected from cyanobacterial bloom events. (9−11) Genotype analysis supports the presence of biosynthesis genes for cyanopeptides beyond microcystins in common cyanobacterial species, including Microcystis, Dolichospermum, and Planktothrix. (12,13) While the potential to produce cyanopeptides beyond microcystins is widely accepted, our knowledge about their abundance, persistence, and toxicity remains largely limited.
One limiting factor regarding our knowledge about these understudied cyanopeptides is the lack of commercially available reference standard materials that are essential for fate and toxicity studies and routine analytical measurements. Alternatively, most studies thus far report only qualitative information or semiquantitative concentrations based on microcystin-LR equivalent units, as this reference material is commercially available. (14−17) Two recent studies used up to six purified cyanopeptolins, microginins, and anabaenopeptins to quantify them directly in lake water from cyanobacterial blooms. (10,18,19) These studies demonstrated that other cyanopeptides can occur in high frequency and comparable concentrations to microcystins and can even reach drinking water treatment plants. (20) However, the availability of such reference standards remains restricted and monitoring only single cyanopeptides can still underestimate exposure to other potentially toxic metabolites during cyanobacterial bloom events. Most studies include only these few cyanopeptides for which reference standards exist but without verifying that these are the most abundant peptides present in the bloom of species of interest. A better understanding of other cyanopeptides would facilitate the prioritization of those compounds for which reference standards need to be made available.
The concentration of cyanopeptides in surface waters defines the exposure side of the risk equation and is typically correlated with the cell abundance of toxin-producing cyanobacteria. Microcystin concentrations were observed to peak in the mid-exponential growth period for Microcystis sp. and Dolichospermum sp. (previously Anabaena). (21,22) Single studies observed similar production dynamics for anabaenopeptins, cyanopeptolins (i.e., anabaenopeptilides), and microginins. (17,22,23) Cyanobacterial growth and microcystin production can be affected by environmental variables, including light intensities, temperature, pH, and in particular nutrient availability, which we focus on herein. (23,24) Nitrogen, phosphorus, and micronutrients are essential elements for cellular functioning and nitrogen itself is also a main molecular component of (cyano)peptides. (24) Cyanobacterial taxa cope differently with limited nutrient availability. Microcystis and Dolichospermum generally thrive well at high phosphate concentrations, and the nitrogen-fixing Dolichospermum are also associated with lower nitrogen concentrations. (25−28) Regarding production dynamics of toxins, most research thus far focused on microcystins. Changes in nitrogen and phosphorous availability affected the regulation of mcy gene expression, total microcystin production, microcystin cell quota, ratios of toxin-producing versus nonproducing cyanobacteria, and varied among different strains of Microcystis. (29−36) Our knowledge on the co-production dynamics of these other cyanopeptides remains sparse, and only a few studies inspected effects on cyanopeptide production beyond microcystins thus far. (17,22,23) Understanding whether the production dynamics are synchronized or independent among different cyanopeptides and how nutrient availability influences their presence across growth stages is not only essential for predicting exposure concentrations but may also shed light on the underlying drivers for cyanobacteria to produce such a complex and metabolically expensive peptides in the first place.
In the presented study, we applied a suspect-screening approach to monitor the co-production dynamics of cyanopeptides across different growth stages and nutrient conditions, including phosphorous, nitrogen, and micronutrient reduction for Microcystis aeruginosa and Dolichospermum flos-aquae. Our results demonstrate that the production of all cyanopeptides was synchronized in M. aeruginosa also for the rarely studied but dominating cyclamides. Abundant cyanopeptides likely co-occur at different growth stages and nutrient conditions and reference standards should be made available in the future to include them in lake monitoring, fate studies, and toxicity testing.

Experimental Section

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Materials

Microcystin reference standards for MC-LR, MC-YR, MC-RR, MC-LF, MC-LA, MC-LW, MC-LY, and Nodularin were obtained from Enzo Life Science (Lausen, Switzerland). Cyanopeptolin A, cyanopeptolin D, anabaenopeptin A, anabaenopeptin NZ857, and oscillamide Y were obtained as bioreagents from CyanoBiotech GmbH (Berlin, Germany). Aerucyclamide A was obtained as a purified bioreagent in dimethyl sulfoxide by Prof. Karl Gademann (University Zurich, Switzerland). (37) Additional materials are listed in the Supporting Information.

Cyanobacterial Cultures

M. aeruginosa PCC7806 was originally isolated from the Braakman reservoir in The Netherlands (1972) and was obtained from the Pasteur Culture Collection of Cyanobacteria (France). D. flos-aquae NIVA-CYA 269/6 was originally isolated from Lake Frøylandsvatnet in Norway (1990) and was obtained from the Norwegian Culture Collection of Algae (NORCCA). We maintained cultures in 100 mL Erlenmeyer flasks in modified WC medium (Table S1) at 20 ± 2 °C and irradiance at 12 μmol photons m–2 s–1 on a 12:12 h light/dark cycle. (38) Before using in an experiment, cultures were maintained in the respective medium over two inoculation cycles where 10–15% inoculum was transferred to fresh medium every three weeks at the later stage of the exponential growth phase. All subculturing and sampling in the experiments described below were performed under sterile conditions.

Effects of Growth Stages and Nutrients

The effects of the growth stage and nutrient concentrations on cyanopeptide production and cell density were evaluated for M. aeruginosa. Cultures were prepared in duplicate in 1 L Schott bottles with 800 mL medium and an initial cell density of (1–3) × 105 cells mL–1. The cultures were kept under continuous aeration. In addition to the standard conditions of the WC medium with a nitrogen to phosphorous ratio of N/P = 20 (1 mmol N L–1, 0.05 mmol P L–1), the effect of increasing phosphorus 10-fold (N/P = 2) and decreasing phosphorus by factor 2 (N/P = 40) were investigated across the growth curve. For cyanopeptide analysis, 15 mL of each bottle was sampled on days 0 and 3, 10 mL on day 6, and 5 mL for the remaining of the growth curve.
In addition, the cyanopeptide production in the late exponential phase was analyzed for M. aeruginosa and D. flos-aquae to compare the cyanopeptide profiles between species and under additional nutrient conditions. The experiments were performed in triplicate in 250 mL Schott bottles containing 150 mL of WC medium with an initial cell density of (9.1–9.8) × 104 and (9.0–9.6) × 104 cells mL–1 for M. aeruginosa and D. flos-aquae, respectively. Besides the standard conditions in WC medium at N/P = 20 (1 mmol N L–1, 0.05 mmol P L–1), 5 different nutrient compositions were investigated: 3-fold increase of phosphorus (+P, N/P = 6.66); decrease of phosphorus by factor 100 (−P, N/P = 2000); decrease of nitrogen by factor 100 (−N, N/P = 0.2); decrease of both phosphorus and nitrogen by factor 100 (−N and −P, N/P = 20); and decrease of micronutrients by factor 100 (−MN) (Table S1). The culture bottles were manually shaken periodically and rearranged randomly to reduce the effects of minor differences in the light field on the culturing shelf. For cyanopeptide analysis, 10 mL of culture was sampled when the cells reached the late exponential phase. In bottles with reduced micronutrients, sampling took place after 40 days as the culture only showed minimal growth during the experiment.
For all experiments, 2 mL was removed every 72 h to determine the number of cells by optical density at 750 nm (Cary Series UV–Vis Spectrophotometer, Agilent Technologies). For the growth curve experiment, the cells were also counted using a Neubauer counting chamber under a light microscope (Leitz Biomed, magnification ×400). At least 100 cells were counted for four subsamples and the average was reported and used to normalize cyanopeptide concentration. A calibration of cell count versus optical density at 750 nm for each nutrient condition was used to convert optical densities to cell numbers (Figure S1). The evolution of cell abundance over time was fit to the Richard model to evaluate the growth curves (39)
(1)
with y(t) being the cell density as log-normalized optical density, log(ODt/OD0), at time t, μ being the growth rate, λ being the time of the lag phase, A being the final cell density as maximum log(ODt/OD0), and ν being a shape parameter set to 1.8. The parameters μ and λ were obtained from the fit resulting in the minimized sum of least square error (Solver function in Microsoft Excel, version 2010).

Cyanopeptide Extraction

The cells were harvested by centrifugation (rcf of 4660g at 10 °C, 10 min, Megafuge 1.0 R, Heraeus Instruments), lyophilized (−40 °C, −3 mbar, 24 h, Lyovac GT2, Leybold), and stored at −20 °C until further analysis. For extraction, the weight of the dry material was recorded and MeOH/H2O (70:30 v/v) was added at a ratio of 5 μL mgdry,wt–1. The suspension was homogenized by vortexing, incubated under sonication (VWR, Ultrasonic cleaner USC-THD, level 6, 10 min), and solids were separated from the supernatant by centrifugation (rcf of 4660g, 10 min). The supernatant was transferred to a new glass vial and the extraction was repeated two more times. The solvent was evaporated from the combined extract under a gentle stream of nitrogen (40 °C, TurboVap LV, Biotage) to reduce the methanol content to less than 5%. The extracts were diluted to a total volume of 3 mL with nanopure water prior to clean-up by solid-phase extraction (SPE) on a 12-fold vacuum extraction box (Visiprep, 12 ports, Sigma Aldrich). The SPE cartridges (Oasis HLB 3 cc, 60 mg) were consecutively conditioned with methanol and water (9 mL each). The extracts were loaded onto the cartridges, washed with 9 mL of nanopure water followed by 9 mL of MeOH/H2O (20:80 v/v) prior to elution with 9 mL MeOH/H2O (85:15 v/v) at a flow rate of 1 mL min–1. The eluted fraction was collected and concentrated to 300 μL by vacuum-assisted evaporation (Syncore Analyst R-12, BÜCHI Labortechnik AG, 40 °C, 120 rpm, 20 mbar). Each volume was adjusted gravimetrically to 1.0 mL MeOH/H2O (10:90 v/v) before analysis. Additionally, empty glass vials were extracted and the extracts were subjected to SPE clean up and concentration serving as method blanks. Cyanopeptide standards and bioreagents were spiked to nanopure water, and these samples were processed in the same manner to evaluate relative recoveries of the sample preparation steps (results in Tables S2 and S3).

Cyanopeptide Analysis

Peptide analysis was performed by high-performance liquid chromatography (Dionex UltiMate3000 RS pump, Thermo Fischer Scientific) with an autosampler (CTC Analytics) coupled to a high-resolution tandem mass spectrometer (HRMS/MS, Q-Exactive-Plus Orbitrap, ThermoFisher Scientific). Chromatographic separation was carried out on an XBridgeTM C18 column (3.5 μm, 2.1 mm × 50 mm, Waters) with precolumn (VanGuard Cartridge, Waters) and inline filter (BGB). The mobile phases consisted of nanopure water (eluent A) and methanol (eluent B), both acidified with formic acid (0.1%). Binary gradient elution was carried out at a flow rate of 200 μL min–1 and increasing eluent B from 10 to 100% between 0 and 27.5 min. The injection volume was 25 μL. Detection of analytes was achieved by HRMS/MS with electrospray ionization (ESI), 320 °C capillary temperature, 4 kV electrospray voltage, and 35 V capillary voltage in a positive ionization mode. Full scan accurate mass spectra were acquired from 200 to 1500 m/z with a nominal resolving power of 140 000 referenced at m/z 250, automated gain control (AGC) of 1 × 106, and maximal injection time of 100 ms with 1 ppm mass accuracy. Data-dependent high-resolution product ion spectra were obtained by HCD at 35% collision energy, at a resolving power of 17 500 at 400 m/z, AGC of 1 × 105 and maximal injection time of 80 ms. For triggering data-dependent MS/MS acquisition, we included an in-house suspect list as detailed in Table S4.

Data Processing

The suspect screening included 712 cyanopeptides in total with 297 microcystins, 149 cyanopeptolins, 38 anabaenopeptins, 18 cyclamides, 61 microginins, 55 cryptophycins, 50 aeruginosins, and 44 other compounds (Table S4). The identification of most cyanopeptides needed to be carried out without available reference standard materials. Thus, a comprehensive data analysis workflow adopted from suspect screening applied to small molecules was used. (40) Spectral libraries do not exist for most suspects, and in silico fragmentation predictions were used to facilitate fragment identification (Mass Frontier 7.0, mMass 5.5.0). Herein, only those cyanopeptides were reported that could be identified as one of the following criteria. A compound was identified as a tentative candidate based on exact mass (<5 ppm mass error), accurate isotopic pattern (idotp > 0.9), and evidence from the fragmentation data; cyanopeptides were identified as confirmed structures when these parameters were in agreement with available reference standards or bioreagents. The comparison of intensity over the m/z range for mass spectrometry fragmentation spectra between confirmed structures (level 1) and cyanobacteria biomass extract was done by plotting head to tail plots using the R packages RMassBank (41) and MSMSsim (42) (Figures S2–S10). Data analysis was performed in RStudio with R version 3.6.1. (43) The HRMS measurement data files were converted to open.mzXML data format using the msconvert tool from ProteoWizard. (44) The data evaluation and extraction of peak areas was performed with Skyline (version 4.1).
The peak area of the selected ion chromatogram was extracted for all identified cyanopeptides. Different charge states (z = 1, z = 2) and adducts (+H, +Na) were considered and for all identified compounds, the M+H was identified as the dominant ion with the exception of microcystins that contain two arginine moieties, here the M+2H was selected for area extraction. The identified cyanopeptides were quantified by external calibration curves of the available reference standard and bioreagent in the range of the analyte concentration present in the samples. Matrix effects on ionization efficiency were considered by standard addition to cyanobacterial extracts. Concentrations were only reported when the peak area was above the limits of quantification (LOQs), defined as 10 times the ratio of the standard deviation of the response-to-slope of the calibration curve. Parameters for matrix effects, relative response factor, LOD, LOQ, and recoveries from sample preparation can be found in Table S2. For those cyanopeptides for which no reference standard or bioreagent was available, we calculated microcystin-LR equivalent units and class-specific equivalents. The microcystin-LR equivalent units were calculated from external calibration with microcystin-LR standard. To calculate the class-specific equivalent units, we calculated the response factor of the calibration slope for all available bioreagents relative to that of microcystin-LR. We multiplied the microcystin-LR equivalent units for each compound by the relative response factor of the structurally most similar bioreagent or standard. All (equivalent) concentrations were normalized either to the number of cells or the dry weight of extracted biomass. The independent student t-test and one-way analysis of variance (ANOVA) followed by Tukey was employed to detect any statistically significant difference in the total cyanopeptide concentration, growth rate, and final cell density by comparison of the 95% confidence intervals (α = 0.05) in RStudio (version 3.6.1).

Results and Discussion

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Co-Production of Cyanopeptides

We investigated the co-production of cyanopeptides in M. aeruginosa and D. flos-aquae by suspect screening of 712 structurally known cyanobacterial peptides, including cyclamides, cyanopeptolins, aeruginosins, microcystins, anabaenopeptins, and microginins. Of these, we tentatively identified 11 cyanopeptides in M. aeruginosa and 17 in D. flos-aquae, and the most abundant metabolites are listed in Table 1 (for compounds with <2% abundance, see Tables S5 and S6). We observed a total cyanopeptide concentration of 0.4 ± 0.1 μmol gdry-wt–1 in M. aeruginosa and 2.0 ± 0.4 μmol gdry-wt–1 in D. flos-aquae for biomass harvested in the late exponential growth phase (WC medium with N/P 20). Since standard reference materials were not available for most cyanopeptides, we used a class-equivalent approach for quantification (Tables S5 and S6). The response factors varied up to 2.5-fold across different microcystin variants and up to 6-fold across all cyanopeptides tested. The class-equivalent approach critically affected quantification compared to microcystin-LR equivalents. For example, the class-equivalent concentrations for cyanopeptolin A and aerucyclamide A were 2.3- and 6-fold higher, respectively, compared to microcystin-LR equivalent units. As long as no true reference materials are available for each compound, we recommend quantification by class equivalents instead of microcystin-LR equivalents.
Table 1. Main Cyanopeptides Tentatively Identified in Cell Extracts of M. aeruginosa and D. flos-aquae
cyanopeptidereferencesmolecular formulaclass equivalentsa (%)MC-LR equivalentsb (%)
Microcystis aeruginosa
aerucyclamide A (37)C24H34N6O4S243 ± 1033 ± 9
aerucyclamide C (37)C24H32N6O5S25 ± 619 ± 5
aerucyclamide B (48)C24H32N6O5S211 ± 39 ± 2
aerucyclamide D (48)C26H30N6O4S33 ± 12 ± 1
total aerucyclamides  82 ± 1263 ± 11
MC-LR (49)C49H74N10O123 ± 110 ± 3
MC-LR-demethyl groupc C48H72N10O121 ± <16 ± 2
total microcystins  4 ± 116 ± 4
cyanopeptolin D (45)C48H76N8O125 ± 17 ± 3
cyanopeptolin A (45)C46H71N10O12H4 ± 18 ± 3
cyanopeptolin C (45)C47H73N8O12H3 ± 13 ± 2
cyanopeptolin B (45)C46H71N8O12H1 ± <13 ± 1
total cyanopeptolins  14 ± 221 ± 5
Dolichospermum flos-aquae
oscillamide Y (50)C45H59N7O1084 ± 2333 ± 8
anabaenopeptin A (51)C44H57N7O107 ± 222 ± 5
anabaenopeptin E groupc C42H62N10O92 ± <110 ± 2
anabaenopeptin B (52)C41H60N10O91 ± <17 ± 1
total anabaenopeptins  94 ± 2372 ± 10
MC-YR-groupc C52H72N10O132 ± <18 ± 1
MC-LR-demethyl groupc C48H72N10O122 ± <17 ± 1
MC-LR (49)C49H74N10O121 ± <13 ± <1
MC-HtyR groupb (53,54)C53H74N10O131 ± <14 ± <1
total microcystins  6 ± <122 ± 2
a

Quantitative analysis based on selected positive ion chromatograms of the protonated peptides. Relative amounts of variants smaller than two percent of the total were not included. Quantification was based on class equivalent (mol mg–1 dry weight of biomass).

b

Quantification was based on Microcystin-LR equivalents.

c

Isobaric compounds, see Table S7.

Based on class-equivalent quantification, cyclamides contributed 82%, cyanopeptolins 14%, and microcystins 4% to the total cyanopeptide pool of M. aeruginosa. The class of cyclamides was dominated by aerucyclamide A, followed by aerucyclamide C, B, and D, which are all cyclic hexapeptides characterized by three azole or azoline rings. The sulfoxide of aerucyclamide D was also detected, which can be formed upon post-translational methionine oxidation. Aerucyclamide A was with 43% most abundant cyanopeptide overall and has, to our current knowledge, not been included in the studies of production dynamics to date. The class of cyanopeptolins was dominated by cyanopeptolin D followed by cyanopeptolin A, C, and B. Cyanopeptolins are depsipeptides containing the characteristic 3-amino-6-hydroxy-2-piperidone (Ahp) moiety and the four variants differ in one of the six building blocks, where the N,N-dimethyl-lysine of cyanopeptolin D is replaced by arginine, N-methyl-lysine, or lysine, respectively. (45−47) The class of microcystins was dominated by microcystin-LR, followed by the demethyl-microcystin-LR-group. Note that the demethyl-microcystin-LR-group represents isobaric compounds with C48H72N10O12. Details of all isobaric groups reported herein can be found in Table S7. Overall, the abundant cyanopeptides observed here are comparable to a recent report on the global metabolome of bloom-forming Microcystis spp. (14)
In D. flos-aquae, anabaenopeptins contributed 94% and microcystins 6% to the total cyanopeptide pool based on class equivalents. The class of anabaenopeptins was dominated by oscillamide Y (83%) and a smaller contribution of anabaenopeptin A (7%), the isobaric group of anabaenopeptin E (2%, C42H62N10O9 see Table S6) and anabaenopeptin B (1%). We confirmed the presence of oscillamide Y and not its isobaric analogue anabaenopeptin NZ857 by analysis of the secondary fragmentation (see Figures S6 and S7). Anabaenopeptins are five-membered cyclic peptides with the ureido bond connecting the primary amine of lysine with the primary amine of the neighboring amino acid and lysine’s epsilon-amine with the carboxyl group of the C terminal amino acid to form a urea moiety. Oscillamide Y and anabaenopeptin A contain, respectively, an L-Phe and L-Tyr, which is replaced for L-Arg in the anabaenopeptin B and E group. Additional variation is mostly attributed to changes in the aliphatic parts. The class of microcystins was dominated by microcystin-YR (2%), followed by the demethyl-microcystin-LR-group (2%) and microcystin-LR (1%). We further evaluated the cyanopeptide production dynamics along the growth curve and then compared cyanopeptide profiles under different nutrient conditions.

Production Dynamics along the Growth Curve

We investigated the change of peptide production relative to cell abundance and across the growth phases of M. aeruginosa in batch cultures. We used three different initial phosphorous concentrations of 0.5, 0.05, and 0.025 mmol L–1 while the initial nitrogen content was kept constant at 1 mmol L–1 resulting in N/P ratios of 2, 20, and 40, respectively. Previous studies reported that extracellular concentrations typically account for a small fraction of the total cyanopeptide pool, even in the stationary phase when the release of intracellular peptides into the medium can be higher due to cell lysis; hence, we focused on intracellular cyanopeptide concentrations herein. (55,56)
Data in Figure 1A show the growth curve of M. aeruginosa as normalized cell abundance and the growth behavior was comparable under the three N/P conditions with slightly lower total final cell abundance in the 0.5 mmol L–1 conditions (non-normalized data Figure S11). Microcystis have been shown to grow equally well with comparable growth rates across a wide range of phosphorus concentrations (1.75 μmol L–1 to 2 mmol L–1). (57,58) Data in Figure 1B show that the concentration of total cyanopeptides (nmol mL–1) directly correlated with cell abundance and the cyanopeptide production per cell remained stable between 0.025 and 0.5 mmol P L–1. The correlation of cyanobacteria biovolume and microcystin production has been regularly reported. (25,59,60) These observations were supported by the fact that the mcyD gene, one of the genes involved in microcystin biosynthesis, was upregulated in M. aeruginosa when phosphorus concentration was decreased in batch cultures. (58) Here, we demonstrate that the correlation also holds for the production dynamics of other cyanopeptides, including cyclamides and cyanopeptolins, that were co-produced (Figure S12). Even though the other cyanopeptide classes are synthetized by different gene clusters, these findings raise the question of whether the production dynamics of less studied cyanopeptides are regulated in a similar manner to microcystins.

Figure 1

Figure 1. (A) Growth curves of M. aeruginosa as log-normalized cell abundance (log Ct/C0) for batch experiments in a medium with 1 mmol L–1 nitrogen and at three total phosphorous concentrations being 0.50 mmol L–1 (N/P = 2), 0.05 mmol L–1 (N/P = 20), and 0.025 mmol L–1 (N/P = 40). The growth parameters μ being the exponential growth rate per day and λ being the lag time before exponential growth in days were obtained by fitting to the Richard model and are listed in the insert. (B) Total cyanopeptide concentrations in nmol mL–1 cyanopeptide class equivalence relative to total cell abundance. The slope represents the cyanopeptide production rate in fmol per cell and parameters of the linear regression are listed in the insert.

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We further investigated cyanopeptide production dynamics across the growth phases. Data in Figure 2 show the cyanopeptide concentrations per cell across the growth phases at an initial phosphorous concentration of 0.05 mmol L–1 (N/P 20). We observed a slight increase of cellular quotas in the mid-exponential phase of the growth curve for the total cyanopeptide concentration, total microcystins, and total cyclamides. The production of no particular cyanopeptide was favored depending on the growth stages and suggested synchronic production along with microcystins. Comparable results were obtained for the other growth conditions (N/P 2 and 40, Figure S13). Peak production in the mid-exponential phase was previously reported for microcystins, (21,23,61) but only two studies considered the production of other cyanopeptides over the growth stages thus far and none of them have considered cyclamides. (17,22) Carneiro et al. also observed synchronized production for microcystins and microginins but without significant change across the growth cycle of a Microcystis field isolate. (17) On the other hand, Repka et al. observed peak production for microcystins in the mid-exponential phase while anabaenopeptin production peak later in the late stationary phase using Anabaena 90. (22) Our data suggest that differences in production dynamics across the growth phases vary not only between genera but also between species. An improved understanding when cyanopeptides are produced and how they may covary will also facilitate hypotheses about the biological function of these complex molecules.

Figure 2

Figure 2. Cyanopeptide concentration per cell in class equivalents over the growth curve for M. aeruginosa for the total production of cyanopeptides (A) and by cyanopeptide class of cyclamides (B), microcystins (C), and cyanopeptolins (D). The shown chemical structures are representative compounds for each cyanopeptide class: aerucyclamide A, microcystin-LR, and cyanopeptolin A, but the shown concentration values represent the sum of all identified members for each class.

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Nutrient Effects on Cyanopeptide Production Dynamics

We further investigated the effect of different nutrient concentrations on the cyanopeptide production dynamics for M. aeruginosa and D. flos-aquae. Across all experiments, we tested nutrient ranges from 0.5 μM to 0.5 mM phosphorous (0.02–16 mgP L–1) and 10 μM to 1 mM nitrogen (0.7–71 mgN L–1). Data in Figure 3 show that the reduction of nutrients always reduced the growth rate (μ) and final cell density (A) for both species. For M. aeruginosa, the decrease of nitrogen alone and together with phosphorous significantly decrease the final cell density by 86% (p < 0.0001) and the specific growth rate by 84% (p = 0.025). The decrease of only phosphorous reduced these growth parameters to a lesser extent (by 33 and 22%, respectively), suggesting that nitrogen was the most limiting growth factor for M. aeruginosa under these conditions. It has previously been shown that nitrogen limitation has a more severe effect on cyanobacterial growth, especially for non-nitrogen-fixing cyanobacteria such as M. aeruginosa. (62) Also, cyanobacteria can adapt to reduced phosphorous availability in surface waters by upregulating specific pathways. Upregulation of transporters responsible for phosphorous storage has been reported to facilitate phosphate storage. (63,64) It was also reported that phosphate limitations can upregulate sulfate-binding protein and permease protein synthesis, suggesting that cyanobacteria can switch to sulfolipids in place of phospholipids to reduce cellular phosphorus quotas. (32) When micronutrients were reduced, we observed a drastic reduction of growth, an increased lag phase to 33 days, and color change to yellow as a sign of cell apoptosis for M. aeruginosa. While the effects on D. flos-aquae were less severe, micronutrient reduction also reduced the final cell density by 52% and the growth rate by 23%. Trace metals are essential to living organisms as cofactors and phototrophic organisms such as cyanobacteria have relatively high trace metal requirements for optimal growth since metal cofactors are part of the photosynthetic apparatus. (65)

Figure 3

Figure 3. Fitted growth curves of (A) M. aeruginosa and (B) D. flos-aquae as log-normalized cell abundance (log Ct/C0) for batch experiments in modified WC medium at six different nutrient concentrations, including the reference conditions with 1 mmol N L–1 and 0.05 mmol P L–1 (control, black), 3-fold increase of P (+P, purple), 100-fold decrease of P (−P, blue), 100-fold decrease of N (−N, green), 100-fold decrease of P and N (−N and −P, orange), and 100-fold decrease of micronutrients (−MN, red). The growth parameters obtained by fitting the Richard model are indicated with μ being the exponential growth rate per day and λ being the lag time before exponential growth in days.

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Nutrient reduction is not only expected to affect cell proliferation but also the production of secondary metabolites. Here, we investigated the effect of nutrient limitation on cyanopeptide production by analyzing biomass in the late exponential phase (or at day 40 for M. aeruginosa under reduced micronutrient conditions where the stationary phase was not reached). Data in Figure 4 show the total cyanopeptide concentrations in nmol class equivalents normalized to the dry weight of analyzed biomass. The total production of cyanopeptides ranged in the hundreds of nmol mgdry-wt–1 for M. aeruginosa and in the thousands of nmol mgdry-wt–1 for D. flos-aquae. While reduction of nutrients always reduced growth significantly, only reduction of phosphorus and micronutrients from 50 to 0.5 μM significantly reduced cyanopeptide production by M. aeruginosa (t-test, p = 0.0008 and 0.0001, respectively). Tonk et al. also observed that the production rate by M. aeruginosa of microcystin-LR and three cyanopeptolins decreased when lowering phosphate availability from 3 to 0.03 μM. (23) Our data demonstrates that this effects also holds for the production of the highly abundant cyclamides and is not apparent at higher P-availability (from 25 to 50 μM, Figure 1B). Under severe phosphorous limitation, upregulation of phosphorous transport by Microcystis may be carried out to the expense of cyanopeptide production as both processes are considered to be metabolically expensive. (63,64)

Figure 4

Figure 4. Total cyanopeptide concentration in nmol class equivalent per dry weight for (A) M. aeruginosa PCC7806 and (B) D. flos-aquae under six different nutrient conditions, including the reference conditions with 1 mmol N L–1 and 0.05 mmol P L–1 and enhanced total phosphorous (+P, by factor 3), reduced total phosphorous (−P, by factor 100), reduced total nitrogen (−N, by factor 100), reduced total phosphorous and nitrogen (both −N and −P by factor 100), and reduced micronutrient concentration (−MN by factor 100) relative to the control conditions (WC medium). The pie charts represent the cyanopeptide profile with relative contribution of cyclamides (blue), cyanopeptolins (green), microcystins (yellow), and anabaenopeptins (purple). p-Values of t-test from comparison to the control conditions are listed. *p-Value < 0.1 and **p-value < 0.05.

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While all conditions with reduced nutrient availability significantly reduced growth also for D. flos-aquae, only reduction of nitrogen significantly reduced cyanopeptide production. Previously, a negative effect of nitrogen reduction had only been reported for microcystin production. (21,63,66,67) Here, we demonstrate that the same relationship holds true also for anabaenopeptins. These findings are consistent with the nitrogen requirements for cyanopeptide synthesis, as nitrogen is not only an essential nutrient needed by the enzymes involved in cyanopeptide production but is also a key building block of these N-rich compounds (C/N ratio of 4–7). (68) Furthermore, previous work demonstrated that reduced nitrogen availability resulted in a lower transcript abundance of the microcystin synthetase genes (mcyA–mcyE) for M. aeruginosa spp. (32) We hypothesize that anabaenopeptin synthetase genes may be similarly regulated when nitrogen is limited. Reducing phosphorous availability to 0.5 μM had no observable effect on the cyanopeptide production for D. flos-aquae, which is in agreement with a previous study that reported an effect on anabaenopeptin production only at strong limitation at 0.1–1 μM for Anabaena 90. (22) We observed that the cyanopeptide profile for D. flos-aquae remained rather constant across different nutrient conditions, with anabaenopeptins being the dominant peptide family (94%), followed by microcystins (6%) and a minor contribution of cyanopeptolins (<1%) (pie chart insert in Figure 4B). The cyanopeptide profile of M. aeruginosa changed under nutrient limiting conditions and we observed a consistent increase of cyanopeptolins (from 16 to 29%) and a decrease of cyclamides (from 80 to 65%) while the contribution of microcystins remained comparable (4–6%, pie chart inserts in Figure 4A).

Implications

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Thus far, the knowledge on production dynamics of cyanopeptide beyond microcystins remains limited. Here, we demonstrate that cellular quotas of M. aeruginosa (PCC7806) were dominated by cyclamides, a class of cyanopeptide that has not been included in studies of production dynamics before. The production of no particular cyanopeptide was favored depending on the growth stages and suggested synchronic production along with microcystins. The results demonstrate that M. aeruginosa maintained similar relative concentrations of all cyanopeptides across different peptide classes. We can hypothesize the reason why cyanobacteria producing different cyanopeptides is not related to requirements that change during the growth cycle. Our observations further suggest that M. aeruginosa and D. flos-aquae respond differently to reduced phosphorous, nitrogen, and micronutrient availability, not only regarding their growth behavior but also regarding their cyanopeptide production. Finding the cause of the different effects of nutrient conditions on cyanopeptide production dynamics between species remains challenging because the underlying motivation why cyanobacteria produce these metabolites in the first place remains poorly understood. Our data suggest that the production dynamics of less studied cyanopeptides are in part comparable to those of the well-known microcystins, and one can hypothesize that distinct cyanopeptides serve different functions for D. flos-aquae, rich in anabaenopeptins, and M. aeruginosa, rich in cyclamides and cyanopeptolins.
While the quantification of many cyanopeptides is not possible due to the lack of reference standard materials, the class-equivalent approach presented here determined concentrations more accurately than the more common microcystin-LR equivalent approach. While the microcystin-LR equivalent approach is more widely available, the response in mass spectrometry analysis can vary up to 6-fold for other cyanopeptides, which translates into false quantification of the same magnitude. The class-equivalent approach provides a more accurate representation of the absolute and relative contribution of individual cyanopeptides and peptide classes. From the large target list of more than 700 structurally known cyanopeptides, we herein identified 24 different cyanopeptides produced by these two common bloom-forming strains; M. aeruginosa and D. flos-aquae. These less studied cyanopeptides should be prioritized and commercially reference standards should be made available to encourage more studies on their occurrence in blooms, persistence, and potential toxicity.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.est.9b07334.

  • Cyanopeptide suspect list, fragmentation spectra, and details on culturing and analytical details (PDF)

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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
  • Author
    • Regiane Natumi - Department of Environmental Chemistry, Swiss Federal Institute of Aquatic Science and Technology (Eawag), 8600 Dübendorf, Switzerland
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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Funding of the Marie Curie Innovative Training Network “Natural Toxins and Drinking Water Quality—From Source to Tap (NaToxAq)” (Grant No. 722493) by the European Commission is gratefully acknowledged. We thank Martin Jones for improving the cyanopeptide database and valuable discussions, Marta Reyes and Francesco Pomati for culturing support, Evelyn Vonwyl and Birgit Beck for experimental assistance, and Jennifer Schollée for data analysis support.

References

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    Welker, Martin; Brunke, Matthias; Preussel, Karina; Lippert, Indra; Von Doehren, Hans
    Microbiology (Reading, United Kingdom) (2004), 150 (6), 1785-1796CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
    Microcystis sp. has been recognized in recent years as a producer of a high no. of secondary metabolites. Among these, peptides that are produced by the nonribosomal peptide synthetase pathway often show bioactivity or are toxic to humans. The prodn. of particular peptides is specific for individual Microcystis clones, allowing their characterization as chemotypes by analyzing the peptidome. The authors studied the in situ diversity of peptides and chemotypes in Microcystis communities from lakes in and around Berlin, Germany, by direct anal. of individual colonies by MALDI-TOF mass spectrometry. From 165 colonies analyzed a total of 46 individual peptides could be identified, 21 of which have not been described previously. For six of the new peptides the structures could be elucidated from fragment patterns, while for others only a preliminary classification could be achieved. In most colonies, two to ten individual peptides were detected. In 19 colonies, 16 of which were identified as M. wesenbergii, no peptide metabolites could be detected. The peptide data of 146 colonies were subjected to an ordination (principal component anal.). The principal components were clearly formed by the microcystin variants Mcyst-LR, -RR and -YR, anabaenopeptins B and E/F, a putative microviridin, and a new cyanopeptolin. In the resulting ordination plots most colonies were grouped into five distinct groups, while 40 colonies scattered widely outside these groups. In some cases colonies from different lakes clustered closely, indicating the presence of similar chemotypes in the resp. samples. With respect to colony morphol. no clear correlation between a chemotype and a morphospecies could be established, but M. aeruginosa, for example, was found to produce predominantly microcystins. In contrast, M. ichthyoblabe colonies were mostly neg. for microcystins and instead produced anabaenopeptins. The no. of peptides detected in a limited no. of samples and the various combinations of peptides in individual Microcystis colonies highlights the immense metabolic potential and diversity of this genus.
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  10. 10
    Beversdorf, L. J.; Weirich, C. A.; Bartlett, S. L.; Miller, T. R. Variable cyanobacterial toxin and metabolite profiles across six eutrophic lakes of differing physiochemical characteristics. Toxins 2017, 9, 62,  DOI: 10.3390/toxins9020062
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    10
    Variable cyanobacterial toxin and metabolite profiles across six eutrophic lakes of differing physiochemical characteristics
    Beversdorf, Lucas J.; Weirich, Chelsea A.; Bartlett, Sarah L.; Miller, Todd. R.
    Toxins (2017), 9 (2), 62/1-62/21CODEN: TOXIB7; ISSN:2072-6651. (MDPI AG)
    Future sustainability of freshwater resources is seriously threatened due to the presence of harmful cyanobacterial blooms, and yet, the no., extent, and distribution of most cyanobacterial toxins-including "emerging" toxins and other bioactive compds.-are poorly understood. We measured 15 cyanobacterial compds.-including four microcystins (MC), saxitoxin (SXT), cylindrospermopsin (CYL), anatoxin-a (ATX) and homo-anatoxin-a (hATX), two anabaenopeptins (Apt), three cyanopeptolins (Cpt), microginin (Mgn), and nodularin (NOD)-in six freshwater lakes that regularly experience noxious cHABs. MC, a human liver toxin, was present in all six lakes and was detected in 80% of all samples. Similarly, Apt, Cpt, and Mgn were detected in all lakes in roughly 86%, 50%, and 35% of all samples, resp. Despite being a notable brackish water toxin, NOD was detected in the two shallowest lakes-Wingra (4.3 m) and Koshkonong (2.1 m). All compds. were highly variable temporally, and spatially. Metabolite profiles were significantly different between lakes suggesting lake characteristics influenced the cyanobacterial community and/or metabolite prodn. Understanding how cyanobacterial toxins are distributed across eutrophic lakes may shed light onto the ecol. function of these metabolites, provide valuable information for their remediation and removal, and aid in the protection of public health.
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  11. 11
    Bogialli, S.; Bortolini, C.; Di Gangi, I. M.; Di Gregorio, F. N.; Lucentini, L.; Favaro, G.; Pastore, P. Liquid chromatography-high resolution mass spectrometric methods for the surveillance monitoring of cyanotoxins in freshwaters. Talanta 2017, 170, 322– 330,  DOI: 10.1016/j.talanta.2017.04.033
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    11
    Liquid chromatography-high resolution mass spectrometric methods for the surveillance monitoring of cyanotoxins in freshwaters
    Bogialli, Sara; Bortolini, Claudio; Di Gangi, Iole Maria; Di Gregorio, Federica Nigro; Lucentini, Luca; Favaro, Gabriella; Pastore, Paolo
    Talanta (2017), 170 (), 322-330CODEN: TLNTA2; ISSN:0039-9140. (Elsevier B.V.)
    A comprehensive risk management on human exposure to cyanotoxins, whose prodn. is actually unpredictable, is limited by reliable anal. tools for monitoring as many toxic algal metabolites as possible. Two anal. approaches based on a LC-QTOF system for target anal. and suspect screening of cyanotoxins in freshwater were presented. A database with 369 compds. belonging to cyanobacterial metabolites was developed and used for a retrospective data anal. based on high resoln. mass spectrometry (HRMS). HRMS fragmentation of the suspect cyanotoxin precursor ions was subsequently performed for correctly identifying the specific variants. Alternatively, an automatic tandem HRMS anal. tailored for cyanotoxins was performed in a single chromatog. run, using the developed database as a preferred precursor ions list. Twenty-five exts. of surface and drinking waters contaminated by cyanobacteria were processed. The identification of seven uncommon microcystins (M(O)R, MC-FR, MSer7-YR, D-Asp3MSer7-LR, MSer7-LR, dmAdda-LR and dmAdda-YR) and 6 anabaenopeptins (A, B, F, MM850, MM864, oscyllamide Y) was reported. Several isobaric variants, fully sepd. by chromatog., were pointed out. The developed methods are proposed to be used by environmental and health agencies for strengthening the surveillance monitoring of cyanotoxins in water.
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  12. 12
    Kurmayer, R.; Deng, L.; Entfellner, E. Role of toxic and bioactive secondary metabolites in colonization and bloom formation by filamentous cyanobacteria Planktothrix. Harmful Algae 2016, 54, 69– 86,  DOI: 10.1016/j.hal.2016.01.004
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    12
    Role of toxic and bioactive secondary metabolites in colonization and bloom formation by filamentous cyanobacteria Planktothrix
    Kurmayer, Rainer; Deng, Li; Entfellner, Elisabeth
    Harmful Algae (2016), 54 (), 69-86CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
    A review. Bloom-forming cyanobacteria Planktothrix agardhii and P. rubescens are regularly involved in the occurrence of cyanotoxin in lakes and reservoirs. Besides microcystins (MCs), which inhibit eukaryotic protein phosphatase 1 and 2A, several families of bioactive peptides are produced, thereby resulting in impressive secondary metabolite structural diversity. This review will focus on the current knowledge of the phylogeny, morphol., and ecophysiol. adaptations of Planktothrix as well as the toxins and bioactive peptides produced. The relatively well studied ecophysiol. adaptations (buoyancy, shade tolerance, nutrient storage capacity) can partly explain the invasiveness of this group of cyanobacteria that bloom within short periods (weeks to months). The more recent elucidation of the genetic basis of toxin and bioactive peptide synthesis paved the way for investigating its regulation both in the lab. using cell cultures as well as under field conditions. The high frequency of several toxin and bioactive peptide synthesis genes obsd. within P. agardhii and P. rubescens, but not for other Planktothrix species (e.g. P. pseudagardhii), suggests a potential functional linkage between bioactive peptide prodn. and the colonization potential and possible dominance in habitats. It is hypothesized that, through toxin and bioactive peptide prodn., Planktothrix act as a niche constructor at the ecosystem scale, possibly resulting in an even higher ability to monopolize resources, pos. feedback loops, and resilience under stable environmental conditions. Thus, refocusing harmful algal bloom management by integrating ecol. and phylogenetic factors acting on toxin and bioactive peptide synthesis gene distribution and concns. could increase the predictability of the risks originating from Planktothrix blooms.
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  13. 13
    Otten, T. G.; Paerl, H. W.; Dreher, T. W.; Kimmerer, W. J.; Parker, A. E. The molecular ecology of Microcystis sp blooms in the San Francisco Estuary. Environ. Microbiol. 2017, 19, 3619– 3637,  DOI: 10.1111/1462-2920.13860
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    13
    The molecular ecology of Microcystis sp. blooms in the San Francisco Estuary
    Otten, Timothy G.; Paerl, Hans W.; Dreher, Theo W.; Kimmerer, Wim J.; Parker, Alexander E.
    Environmental Microbiology (2017), 19 (9), 3619-3637CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
    Summary : Harmful blooms of the cyanobacterium Microcystis sp. have become increasingly pervasive in the San Francisco Estuary Delta (USA) since the early 2000s and their rise has coincided with substantial decreases in several important fish species. Direct and indirect effects Microcystis blooms may have on the Delta food web were investigated. The Microcystis population was tracked for 2 years at six sites throughout the Delta using quant. PCR. High-throughput amplicon sequencing and colony PCR sequencing revealed the presence of 10 different strains of Microcystis, including 6 different microcystin-producing strains. Shotgun metagenomic anal. identified a variety of Microcystis secondary metabolite pathways, including those for the biosynthesis of: aeruginosin, cyanopeptolin, microginin, microviridin and piricyclamide. A sizable redn. was obsd. in microbial community diversity during a large Microcystis bloom (H' = 0.61) relative to periods preceding (H' = 2.32) or following (H' = 3.71) the bloom. Physicochem. conditions of the water column were stable throughout the bloom period. The elevated abundance of a cyanomyophage with high similarity to previously sequenced isolates known to infect Microcystis sp. was implicated in the bloom's collapse. Network anal. was employed to elucidate synergistic and antagonistic relationships between Microcystis and other bacteria and indicated that only very few taxa were pos. correlated with Microcystis.
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  14. 14
    Le Manach, S.; Duval, C.; Marie, A.; Djediat, C.; Catherine, A.; Edery, M.; Bernard, C.; Marie, B. Global metabolomic characterizations of Microcystis spp. highlights clonal diversity in natural bloom-forming populations and expands metabolite structural diversity. Front. Microbiol. 2019, 10, 791  DOI: 10.3389/fmicb.2019.00791
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    14
    Global Metabolomic Characterizations of Microcystis spp. Highlights Clonal Diversity in Natural Bloom-Forming Populations and Expands Metabolite Structural Diversity
    Le Manach Severine; Duval Charlotte; Marie Arul; Djediat Chakib; Catherine Arnaud; Edery Marc; Bernard Cecile; Marie Benjamin
    Frontiers in microbiology (2019), 10 (), 791 ISSN:1664-302X.
    Cyanobacteria are photosynthetic prokaryotes capable of synthesizing a large variety of secondary metabolites that exhibit significant bioactivity or toxicity. Microcystis constitutes one of the most common cyanobacterial genera, forming the intensive blooms that nowadays arise in freshwater ecosystems worldwide. Species in this genus can produce numerous cyanotoxins (i.e., toxic cyanobacterial metabolites), which can be harmful to human health and aquatic organisms. To better understand variations in cyanotoxin production between clones of Microcystis species, we investigated the diversity of 24 strains isolated from the same blooms or from different populations in various geographical areas. Strains were compared by genotyping with 16S-ITS fragment sequencing and metabolite chemotyping using LC ESI-qTOF mass spectrometry. While genotyping can help to discriminate among different species, the global metabolome analysis revealed clearly discriminating molecular profiles among strains. These profiles could be clustered primarily according to their global metabolite content, then according to their genotype, and finally according to their sampling location. A global molecular network of all metabolites produced by Microcystis species highlights the production of a wide set of chemically diverse metabolites, including a few microcystins, many aeruginosins, microginins, cyanopeptolins, and anabaenopeptins, together with a large set of unknown molecules. These components, which constitute the molecular biodiversity of Microcystis species, still need to be investigated in terms of their structure and potential bioactivites (e.g., toxicity).
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    Sanz, M.; Andreote, A. P. D.; Fiore, M. F.; Dorr, F. A.; Pinto, E. Structural characterization of new peptide variants produced by cyanobacteria from the Brazilian atlantic coastal forest using liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry. Mar. Drugs 2015, 13, 3892– 3919,  DOI: 10.3390/md13063892
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    15
    Structural characterization of new peptide variants produced by cyanobacteria from the Brazilian atlantic coastal forest using liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry
    Sanz, Miriam; Andreote, Ana Paula Dini; Fiore, Marli Fatima; Dorr, Felipe Augusto; Pinto, Ernani
    Marine Drugs (2015), 13 (6), 3892-3919CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
    Cyanobacteria from underexplored and extreme habitats are attracting increasing attention in the search for new bioactive substances. However, cyanobacterial communities from tropical and subtropical regions are still largely unknown, esp. with respect to metabolite prodn. Among the structurally diverse secondary metabolites produced by these organisms, peptides are by far the most frequently described structures. In this work, liq. chromatog./electrospray ionization coupled to high resoln. quadrupole time of- flight tandem mass spectrometry with pos. ion detection was applied to study the peptide profile of a group of cyanobacteria isolated from the Southeastern Brazilian coastal forest. A total of 38 peptides belonging to three different families (anabaenopeptins, aeruginosins, and cyanopeptolins) were detected in the exts. Of the 38 peptides, 37 were detected here for the first time. New structural features were proposed based on mass accuracy data and isotopic patterns derived from full scan and MS/MS spectra. Interestingly, of the 40 surveyed strains only nine were confirmed to be peptide producers; all of these strains belonged to the order Nostocales (three Nostoc sp., two Desmonostoc sp. and four Brasilonema sp.).
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    Mazur-Marzec, H.; Bertos-Fortis, M.; Torunska-Sitarz, A.; Fidor, A.; Legrand, C. Chemical and genetic diversity of Nodularia spumigena from the Baltic Sea. Mar. Drugs 2016, 14, 209  DOI: 10.3390/md14110209
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    16
    Chemical and genetic diversity of Nodularia spumigena from the Baltic Sea
    Mazur-Marzec, Hanna; Bertos-Fortis, Mireia; Torunska-Sitarz, Anna; Fidor, Anna; Legrand, Catherine
    Marine Drugs (2016), 14 (11), 209/1-209/14CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
    Nodularia spumigena is a toxic, filamentous cyanobacterium occurring in brackish waters worldwide, yet forms extensive recurrent blooms in the Baltic Sea. N. spumigena produces several classes of non-ribosomal peptides (NRPs) that are active against several key metabolic enzymes. Previously, strains from geog. distant regions showed distinct NRP metabolic profiles. In this work, conspecific diversity in N. spumigena was studied using chem. and genetic approaches. NRP profiles were detd. in 25 N. spumigena strains isolated in different years and from different locations in the Baltic Sea using liq. chromatog.-tandem mass spectrometry (LC-MS/MS). Genetic diversity was assessed by targeting the phycocyanin intergenic spacer and flanking regions (cpcBA-IGS). Overall, 14 spumigins, 5 aeruginosins, 2 pseudaeruginosins, 2 nodularins, 36 anabaenopeptins, and one new cyanopeptolin-like peptide were identified among the strains. Seven anabaenopeptins were new structures; one cyanopeptolin-like peptide was discovered in N. spumigena for the first time. Based on NRP profiles and cpcBA-IGS sequences, the strains were grouped into two main clusters without apparent influence of year and location, indicating persistent presence of these two subpopulations in the Baltic Sea. This study is a major step in using chem. profiling to explore conspecific diversity with a higher resoln. than with a sole genetic approach.
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    Carneiro, R. L.; Dorr, F. A.; Dorr, F.; Bortoli, S.; Delherbe, N.; Vasquez, M.; Pinto, E. Co-occurrence of microcystin and microginin congeners in Brazilian strains of Microcystis sp. FEMS Microbiol. Ecol. 2012, 82, 692– 702,  DOI: 10.1111/j.1574-6941.2012.01439.x
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    17
    Co-occurrence of microcystin and microginin congeners in Brazilian strains of Microcystis sp.
    Carneiro, Ronaldo Leal; Dorr, Felipe Augusto; Dorr, Fabiane; Bortoli, Stella; Delherbe, Nathalie; Vasquez, Monica; Pinto, Ernani
    FEMS Microbiology Ecology (2012), 82 (3), 692-702CODEN: FMECEZ; ISSN:0168-6496. (Wiley-Blackwell)
    Species of Microcystis are the most common bloom-forming cyanobacteria in several countries. Despite extensive studies regarding the prodn. of bioactive cyanopeptides in this genus, there are limited data on isolated strains from Brazil. Three Microcystis sp. strains were isolated from the Salto Grande Reservoir (LTPNA01, 08 and 09) and studied for the presence of mcy genes, microcystins and other cyanopeptides. Microcystin and microginin prodn. was confirmed in two isolates using high-resoln. tandem mass spectrometry after electrospray ionization (ESI-Q-TOF), and the structures of two new microginin congeners are proposed (MG756 Ahda-Val-Leu-Hty-Tyr and MG770 MeAhda-Val-Leu-Hty-Tyr). The biosynthesis profile of the identified cyanopeptides was evaluated at different growth phases via a newly developed HPLC-UV method. Results demonstrated no substantial differences in the prodn. of microcystins and microginins after data normalization to cell quota, suggesting a constitutive biosynthesis. This study represents the first confirmed co-prodn. of microginins and microcystins in Brazilian strains of Microcystis sp. and highlights the potential of Brazilian cyanobacteria as a source of natural compds. with pharmaceutical interest.
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    Chorus, I.; Sivonen, K.; Codd, G. A.; Börner, T.; Von Doehren, H.; Welker, M.; Dittmann, E.; Claussner, Y.; Christopffersen, K.; Scober, E.; Utliken, H.; Rohrlack, T.; Lyck, S.; Visser, P. M.; Tonk, L.; Dietrich, D. R.; Hoeger, S. J.; Tandeau de Marsac, N.; Iteman, I.; Niesel, V.; Fastner, J.; Grummt, T.; Heinze, R.; Ferreira, A.-H.; Warming-Svendsen, T.; Flieger, I.; Wessel, G.; Rouhiainen, L.; Morrison, L. F. Toxic and Bioactive Peptides in Cyanobacteria—PEPCY Report , 2006.
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    Janssen, E. M. L. Cyanobacterial peptides beyond microcystins - a review on co-occurrence, toxicity, and challenges for risk assessment. Water Res. 2019, 151, 488– 499,  DOI: 10.1016/j.watres.2018.12.048
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    19
    Cyanobacterial peptides beyond microcystins - A review on co-occurrence, toxicity, and challenges for risk assessment
    Janssen, Elisabeth M.-L.
    Water Research (2019), 151 (), 488-499CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
    Cyanobacterial bloom events that produce natural toxins occur in freshwaters across the globe, yet the potential risk of many cyanobacterial metabolites remains mostly unknown. Only microcystins, one class of cyanopeptides, have been studied intensively and the wealth of evidence regarding exposure concns. and toxicity led to their inclusion in risk management frameworks for water quality. However, cyanobacteria produce an incredible diversity of hundreds of cyanopeptides beyond the class of microcystins. The question arises, whether the other cyanopeptides are in fact of no human and ecol. concern or whether these compds. merely received (too) little attention thus far. Current observations suggest that an assessment of their (eco)toxicol. risk is indeed relevant: First, other cyanopeptides, including cyanopeptolins and anabaenopeptins, can occur just as frequently and at similar nanomolar concns. as microcystins in surface waters. Second, cyanopeptolins, anabaenopeptins, aeruginosins and microginins inhibit proteases in the nanomolar range, in contrast to protein phosphatase inhibition by microcystins. Cyanopeptolins, aeruginosins, and aerucyclamide also show toxicity against grazers in the micromolar range comparable to microcystins. The key challenge for a comprehensive risk assessment of cyanopeptides remains their large structural diversity, lack of ref. stds., and high anal. requirements for identification and quantification. One way forward would be a prevalence study to identify the priority candidates of tentatively abundant, persistent, and toxic cyanopeptides to make comprehensive risk assessments more manageable.
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  20. 20
    Beversdorf, L. J.; Rude, K.; Weirich, C. A.; Bartlett, S. L.; Seaman, M.; Kozik, C.; Biese, P.; Gosz, T.; Suha, M.; Stempa, C.; Shaw, C.; Hedman, C.; Piatt, J. J.; Miller, T. R. Analysis of cyanobacterial metabolites in surface and raw drinking waters reveals more than microcystin. Water Res. 2018, 140, 280– 290,  DOI: 10.1016/j.watres.2018.04.032
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    20
    Analysis of cyanobacterial metabolites in surface and raw drinking waters reveals more than microcystin
    Beversdorf, Lucas J.; Rude, Kayla; Weirich, Chelsea A.; Bartlett, Sarah L.; Seaman, Mary; Kozik, Christine; Biese, Peter; Gosz, Timothy; Suha, Michael; Stempa, Christopher; Shaw, Christopher; Hedman, Curtis; Piatt, Joseph J.; Miller, Todd R.
    Water Research (2018), 140 (), 280-290CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
    Freshwater cyanobacterial blooms are becoming increasingly problematic in regions that rely on surface waters for drinking water prodn. Microcystins (MCs) are toxic peptides produced by multiple cyanobacterial genera with a global occurrence. Cyanobacteria also produce a variety of other toxic and/or otherwise bioactive peptides (TBPs) that have gained less attention including cyanopeptolins (Cpts), anabaenopeptins (Apts), and microginins (Mgn). In this study, we compared temporal and spatial trends of four MCs (MCLR, MCRR, MCYR, MCLA), three Cpts (Cpt1020, Cpt1041, Cpt1007), two Apts (AptF, AptB), and Mgn690 in raw drinking water and at six surface water locations above these drinking water intakes in a eutrophic lake. All four MC congeners and five of six TBPs were detected in lake and raw drinking water. Across all samples, MCLR was the most frequently detected metabolite (100% of samples) followed by MCRR (97%) > Cpt1007 (74%) > MCYR (69%) > AptF (67%) > MCLA (61%) > AptB (54%) > Mgn690 (29%) and Cpt1041 (15%). Mean concns. of MCs, Apts, and Cpts into two drinking water intakes were 3.9± 4.7, 0.14± 0.21, and 0.38± 0.92, resp. Mean concns. in surface water were significantly higher (p<0.05) than in drinking water intakes for MCs but not for Cpts and Apts. Temporal trends in MCs, Cpts, and Apts in the two raw drinking water intakes were significantly correlated (p < 0.05) with measures of cell abundance (chlorophyll-a, Microcystis cell d.), UV absorbance, and turbidity in surface water. This study expands current information about cyanobacterial TBPs that occur in lakes and that enter drinking water treatment plants and underscores the need to det. the fate of less studied cyanobacterial metabolites during drinking water treatment that may exacerbate toxicity of more well-known cyanobacterial toxins.
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    Lee, S. J.; Jang, M. H.; Kim, H. S.; Yoon, B. D.; Oh, H. M. Variation of microcystin content of Microcystis aeruginosa relative to medium N: P ratio and growth stage. J. Appl. Microbiol. 2000, 89, 323– 329,  DOI: 10.1046/j.1365-2672.2000.01112.x
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    21
    Variation of microcystin content of Microcystis aeruginosa relative to medium N:P ratio and growth stage
    Lee, S. J.; Jang, M. -H.; Kim, H. -S.; Yoon, B. -D.; Oh, H. -M.
    Journal of Applied Microbiology (2000), 89 (2), 323-329CODEN: JAMIFK; ISSN:1364-5072. (Blackwell Science Ltd.)
    Changes in the microcystin content of Microcystis aeruginosa UTEX 2388 were investigated at several N:P ratios of the medium and various growth stages. Under the P-fixed condition, the microcystin content of the cells changed with different medium N:P ratios, with the highest at 2748 μg g-1 at a N:P ratio of 16 after incubation for 7 d. The microcystin content of M. aeruginosa exhibited a high correlation with the total N content regardless of an N-fixed or P-fixed culture. When the N:P ratio of the medium was fixed to 16:1, the microcystin content of M. aeruginosa at various growth stages was highest at 2191 μg g-1 after an incubation of 4 d and the chlorophyll a content showed a similar tendency. There was a highly significant relationship between the microcystin content of M. aeruginosa and the chlorophyll a concn. in the culture during the incubation. Accordingly, the microcystin content of M. aeruginosa during incubation can be easily estd. and monitored by measuring the in vivo fluorescence changes in the culture.
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    Repka, S.; Koivula, M.; Harjunpa, V.; Rouhiainen, L.; Sivonen, K. Effects of phosphate and light on growth of and bioactive peptide production by the cyanobacterium Anabaena strain 90 and its anabaenopeptilide mutant. Appl. Environ. Microbiol. 2004, 70, 4551– 4560,  DOI: 10.1128/AEM.70.8.4551-4560.2004
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    Effects of phosphate and light on growth of and bioactive peptide production by the cyanobacterium Anabaena strain 90 and its anabaenopeptilide mutant
    Repka, Sari; Koivula, Minna; Harjunpae, Vesa; Rouhiainen, Leo; Sivonen, Kaarina
    Applied and Environmental Microbiology (2004), 70 (8), 4551-4560CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
    Cyanobacteria synthesize several types of bioactive secondary metabolites. Anabaena strain 90 produces three types of bioactive peptides, microcystins (inhibitors of protein phosphatases 1 and 2A), anabaenopeptilides, and anabaenopeptins (serine protease inhibitors). To investigate the role of the anabaenopeptilides in Anabaena, wild-type strain 90 (WT) and its anabaenopeptilide deficient mutant (MU) were cultured with various light and phosphate levels to evaluate the effects and coeffects of these growth factors on the concns. of the three classes of peptides and the growth characteristics. WT and MU grew in comparable ways under the different growth conditions. The total peptide concn. in WT was significantly higher than that in MU (2.5 and 1.4 μg/mg [dry wt.], resp.). Interestingly, the av. concn. of anabaenopeptins was significantly higher in MU than in WT (0.59 and 0.24 μg/mg [dry wt.], resp.). The concn. of microcystins was slightly but not statistically significantly higher in MU than in WT (1.0 and 0.86 μg/mg [dry wt.], resp.). In WT, the highest peptide concns. were usually found after 13 days in cultures grown at medium light intensities (23 μmol m-2 s-1) and with the highest phosphate concns. (2,600 μg liter-1). In MU, the highest peptide concns. were found in 13-day-old cultures grown at medium light intensities (23 μmol m-2 s-1) and with phosphate concns. greater than 100 μg liter-1. The higher concns. of anabaenopeptins in MU may compensate for the absence of anabaenopeptilides. These findings clearly indicate that these compds. may have some linked function in the producer organism, the nature of which remains to be discovered.
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    Tonk, L.; Welker, M.; Huisman, J.; Visser, P. M. Production of cyanopeptolins, anabaenopeptins, and microcystins by the harmful cyanobacteria Anabaena 90 and Microcystis PCC 7806. Harmful Algae 2009, 8, 219– 224,  DOI: 10.1016/j.hal.2008.05.005
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    Production of cyanopeptolins, anabaenopeptins, and microcystins by the harmful cyanobacteria Anabaena 90 and Microcystic PCC 7806
    Tonk, Linda; Welker, Martin; Huisman, Jef; Visser, Petra M.
    Harmful Algae (2009), 8 (2), 219-224CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
    This study investigated the effects of light intensity, temp., and phosphorus limitation on the peptide prodn. of the cyanobacteria Microcystis PCC 7806 and Anabaena 90. Microcystis PCC 7806 produced two microcystin variants and three cyanopeptolins, whereas Anabaena 90 produced four microcystin variants, three anabaenopeptins, and two anabaenopeptilides. Microcystin and cyanopeptolin contents varied by a factor 2-3, whereas the anabaenopeptins and anabaenopeptilides of Anabaena varied more strongly. Under phosphorus limitation, peptide prodn. rates increased with the specific growth rate. The response of peptide prodn. to light intensity and temp. was more complex: in many cases peptide prodn. decreased with specific growth rate. We obsd. compensatory changes of different peptide variants: decreased cyanopeptolin A and C contents were accompanied by increased cyanopeptolin 970 contents, and decreased anabaenopeptin A and C contents were accompanied by increased anabaenopeptilide 90B contents. Compensatory dynamics in peptide prodn. may enable cyanobacteria to sustain stable peptide levels in a variable environment.
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    Dai, R. H.; Wang, P. F.; Jia, P. L.; Zhang, Y.; Chu, X. C.; Wang, Y. F. A review on factors affecting microcystins production by algae in aquatic environments. World J. Microbiol. Biotechnol. 2016, 32, 51  DOI: 10.1007/s11274-015-2003-2
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    A review on factors affecting microcystins production by algae in aquatic environments
    Dai Ruihua; Wang Pinfei; Jia Peili; Zhang Yi; Chu Xincheng; Wang Yifei
    World journal of microbiology & biotechnology (2016), 32 (3), 51 ISSN:.
    Microcystins, a toxin produced by Microcystis aeruginosa have become a global environmental issue in recent years. As a consequence of eutrophication, microcystins have become widely disseminated in drinking water sources, seriously impairing drinking water quality. This review focuses on the relationship between microcystins synthesis and physical, chemical, and biological environmental factors that are significant in controlling their production. Light intensity and temperature are the more important physical factors, and in many cases, an optimum level for these two factors has been observed. Nitrogen and phosphorus are the key chemical factors causing frequent occurrence of harmful algal blooms and microcystins production. The absorption of nutrients and metabolic activities of algae are affected by different concentrations and forms of nitrogen and phosphorus, leading to variations in microcystins production Metal ions and emerging pollutants are other significant chemical factors, whose comprehensive impact is still being studied. Algae can also interact with biological agents like predators and competitors in aquatic environments, and such interactions are suggested to promote MCs production and release. This review further highlights areas that require further research in order to gain a better understanding of microcystins production. It provides a theoretical basis for the control of microcystins production and releasing into aquatic environments.
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    Dolman, A. M.; Rucker, J.; Pick, F. R.; Fastner, J.; Rohrlack, T.; Mischke, U.; Wiedner, C. Cyanobacteria and cyanotoxins: the influence of nitrogen versus phosphorus. PLoS One 2012, 7, e38757  DOI: 10.1371/journal.pone.0038757
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    Cyanobacteria and cyanotoxins: the influence of nitrogen versus phosphorus
    Dolman, Andrew M.; Ruecker, Jacqueline; Pick, Frances R.; Fastner, Jutta; Rohrlack, Thomas; Mischke, Ute; Wiedner, Claudia
    PLoS One (2012), 7 (6), e38757CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    The importance of N vs. P in explaining total cyanobacterial biovolume, the biovolume of specific cyanobacterial taxa, and the incidence of cyanotoxins was detd. for 102 North German lakes, using methods to sep. the effects of joint variation in N and P concn. from those of differential variation in N vs. P. While the pos. relationship between total cyanobacteria biovolume and P concn. disappeared at high P concns., cyanobacteria biovolume increased continually with N concn., indicating potential N limitation in highly P enriched lakes. The biovolumes of all cyanobacterial taxa were higher in lakes with above av. joint NP concns., although the relative biovolumes of some Nostocales were higher in less enriched lakes. Taxa were found to have diverse responses to differential N vs. P concn., and the differences between taxa were not consistent with the hypothesis that potentially N2-fixing Nostocales taxa would be favored in low N relative to P conditions. In particular Aphanizomenon gracile and the subtropical invasive species Cylindrospermopsis raciborskii often reached their highest biovolumes in lakes with high nitrogen relative to phosphorus concn. Concns. of all cyanotoxin groups increased with increasing TP and TN, congruent with the biovolumes of their likely producers. Microcystin concn. was strongly correlated with the biovolume of Planktothrix agardhii but concns. of anatoxin, cylindrospermopsin and paralytic shellfish poison were not strongly related to any individual taxa. Cyanobacteria should not be treated as a single group when considering the potential effects of changes in nutrient loading on phytoplankton community structure and neither should the N2-fixing Nostocales. This is of particular importance when considering the occurrence of cyanotoxins, as the two most abundant potentially toxin producing Nostocales in our study were found in lakes with high N relative to P enrichment.
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    Tromas, N.; Taranu, Z. E.; Martin, B. D.; Willis, A.; Fortin, N.; Greer, C. W.; Shapiro, B. J. Niche separation increases with Genetic distance among bloom-forming cyanobacteria. Front. Microbiol. 2018, 9, 438  DOI: 10.3389/fmicb.2018.00438
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    Niche Separation Increases With Genetic Distance Among Bloom-Forming Cyanobacteria
    Tromas Nicolas; Shapiro B Jesse; Taranu Zofia E; Martin Bryan D; Willis Amy; Willis Amy; Fortin Nathalie; Greer Charles W
    Frontiers in microbiology (2018), 9 (), 438 ISSN:1664-302X.
    Bacterial communities are composed of distinct groups of potentially interacting lineages, each thought to occupy a distinct ecological niche. It remains unclear, however, how quickly niche preference evolves and whether more closely related lineages are more likely to share ecological niches. We addressed these questions by following the dynamics of two bloom-forming cyanobacterial genera over an 8-year time-course in Lake Champlain, Canada, using 16S amplicon sequencing and measurements of several environmental parameters. The two genera, Microcystis (M) and Dolichospermum (D), are frequently observed simultaneously during bloom events and thus have partially overlapping niches. However, the extent of their niche overlap is debated, and it is also unclear to what extent niche partitioning occurs among strains within each genus. To identify strains within each genus, we applied minimum entropy decomposition (MED) to 16S rRNA gene sequences. We confirmed that at a genus level, M and D have different preferences for nitrogen and phosphorus concentrations. Within each genus, we also identified strains differentially associated with temperature, precipitation, and concentrations of nutrients and toxins. In general, niche similarity between strains (as measured by co-occurrence over time) declined with genetic distance. This pattern is consistent with habitat filtering - in which closely related taxa are ecologically similar, and therefore tend to co-occur under similar environmental conditions. In contrast with this general pattern, similarity in certain niche dimensions (notably particulate nitrogen and phosphorus) did not decline linearly with genetic distance, and instead showed a complex polynomial relationship. This observation suggests the importance of processes other than habitat filtering - such as competition between closely related taxa, or convergent trait evolution in distantly related taxa - in shaping particular traits in microbial communities.
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    Xie, L. Q.; Xie, P.; Li, S. X.; Tang, H. J.; Liu, H. The low TN: TP ratio, a cause or a result of Microcystis blooms?. Water Res. 2003, 37, 2073– 2080,  DOI: 10.1016/S0043-1354(02)00532-8
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    27
    The low TN:TP ratio, a cause or a result of Microcystis blooms?
    Xie, Liqiang; Xie, Ping; Li, Sixin; Tang, Huijuan; Liu, Hong
    Water Research (2003), 37 (9), 2073-2080CODEN: WATRAG; ISSN:0043-1354. (Elsevier Science Ltd.)
    An enclosure expt. in the shallow, subtropical Lake Donghu, China, was performed in the summer of 2001 to examine the effect of TN:TP (total P) ratios and P-redn. on the occurrence of Microcystis blooms. The treatments were performed with enough amts. of N but with different amts. of P in the water column and sediment. Microcystis blooms occurred in the enclosures either with an initial TN:TP <29 or TN:TP>29 where the nutrients (N, P) were high enough. Microcystis blooms never occurred in the treatments with low P concn. in spite of the presence of sufficient N. The P-rich sediments served as an important source for the P supply in the water column, and such a process was activated greatly by the outburst of Microcystis blooms which pumped up selectively P from the sediments and thus decreased the TN:TP ratios. Therefore, the low TN:TP ratio is not a cause but rather a result of Microcystis blooms.
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    Chia, M. A.; Jankowiak, J. G.; Kramer, B. J.; Goleski, J. A.; Huang, I.-S.; Zimba, P. V.; do Carmo Bittencourt-Oliveira, M.; Gobler, C. J. Succession and toxicity of Microcystis and Anabaena (Dolichospermum) blooms are controlled by nutrient-dependent allelopathic interactions. Harmful Algae 2018, 74, 67– 77,  DOI: 10.1016/j.hal.2018.03.002
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    Succession and toxicity of Microcystis and Anabaena (Dolichospermum) blooms are controlled by nutrient-dependent allelopathic interactions
    Chia, Mathias A.; Jankowiak, Jennifer G.; Kramer, Benjamin J.; Goleski, Jennifer A.; Huang, I.-Shuo; Zimba, Paul V.; Bittencourt-Oliveira, Maria do Carmo; Gobler, Christopher J.
    Harmful Algae (2018), 74 (), 67-77CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
    Microcystis and Anabaena (Dolichospermum) are among the most toxic cyanobacterial genera and often succeed each other during harmful algal blooms. The role allelopathy plays in the succession of these genera is not fully understood. The allelopathic interactions of six strains of Microcystis and Anabaena under different nutrient conditions in co-culture and in culture-filtrate expts. were investigated. Microcystis strains significantly reduced the growth of Anabaena strains in mixed cultures with direct cell-to-cell contact and high nutrient levels. Cell-free filtrate from Microcystis cultures proved equally potent in suppressing the growth of nutrient replete Anabaena cultures while also significantly reducing anatoxin-a prodn. Allelopathic interactions between Microcystis and Anabaena were, however, partly dependent on ambient nutrient levels. Anabaena dominated under low N conditions and Microcystis dominated under nutrient replete and low P during which allelochems. caused the complete suppression of nitrogen fixation by Anabaena and stimulated glutathione S-transferase activity. The microcystin content of Microcystis was lowered with decreasing N and the presence of Anabaena decreased it further under low P and high nutrient conditions. Collectively, these results indicate that strong allelopathic interactions between Microcystis and Anabaena are closely intertwined with the availability of nutrients and that allelopathy may contribute to the succession, nitrogen availability, and toxicity of cyanobacterial blooms.
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    Oh, H. M.; Lee, S. J.; Jang, M. H.; Yoon, B. D. Microcystin production by Microcystis aeruginosa in a phosphorus-limited chemostat. Appl. Environ. Microbiol. 2000, 66, 176– 179,  DOI: 10.1128/AEM.66.1.176-179.2000
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    Microcystin production by Microcystis aeruginosa in a phosphorus-limited chemostat
    Oh, Hee-Mock; Lee, Seog June; Jang, Min-Ho; Yoon, Byung-Dae
    Applied and Environmental Microbiology (2000), 66 (1), 176-179CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
    The prodn. of microcystins (MC) from Microcystis aeruginosa UTEX 2388 was investigated in a P-limited continuous culture. MC (MC-LR, MC-RR, and MC-YR) from lyophilized M. aeruginosa were extd. with 5% acetic acid, purified by a Sep-Pak C18 cartridge, and then analyzed by high-performance liq. chromatog. with a UV detector and Nucleosil C18 reverse-phase column. The specific growth rate (μ) of M. aeruginosa was within the range of 0.1 to 0.8/day and was a function of the cellular P content under a P limitation. The N/P at. ratio of steady-state cells in a P-limited medium varied from 24 to 15 with an increasing μ. The MC-LR and MC-RR contents on a dry wt. basis were highest at μ of 0.1/day at 339 and 774 μg g-1, resp., while MC-YR was not detected. The MC content of M. aeruginosa was higher at a lower μ, whereas the MC-producing rate was linearly proportional to μ. The C fixation rate at an ambient irradiance (160 microeinsteins m-2 s-1) increased with μ. The ratios of the MC-producing rate to the C fixation rate were higher at a lower μ. Accordingly, the growth of M. aeruginosa was reduced under a P limitation due to a low C fixation rate, whereas the MC content was higher. Consequently, increases in the MC content per dry wt. along with the prodn. of the more toxic form, MC-LR, were obsd. under more P-limited conditions.
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    Pimentel, J. S. M.; Giani, A. Microcystin production and regulation under nutrient stress conditions in toxic Microcystis strains. Appl. Environ. Microbiol. 2014, 80, 5836– 5843,  DOI: 10.1128/AEM.01009-14
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    30
    Microcystin production and regulation under nutrient stress conditions in toxic Microcystis strains
    Pimentel, Juliana S. M.; Giani, Alessandra
    Applied and Environmental Microbiology (2014), 80 (18), 5836-5843, 9 pp.CODEN: AEMIDF; ISSN:1098-5336. (American Society for Microbiology)
    Microcystin is a common and well-known cyanobacterial toxin whose intracellular role is still under investigation. Increasing knowledge on microcystin gene expression and regulation can contribute to the understanding of its putative cellular function. In this work, reverse transcription-quant. PCR (RT-qPCR) was used to investigate the transcriptional response of the mcyD gene to nitrogen (nitrate and ammonium) and phosphorus limitation in two toxic Microcystis strains. The existence of a direct correlation between transcripts of mcyD and ntcA genes was also identified. In previous studies, NtcA (global nitrogen regulator) has been described as a potential component in the control of microcystin biosynthesis. This research showed that stress agents linked to nutrient deprivation could lead to a significant increase of microcystin prodn. in both strains studied. The more toxic strain proved to be more resistant to nutrient limitation. The similar outcomes of mcyD regulation obsd. for all nutrients suggest that this response can be linked to oxidative stress of cells undergoing adverse growth conditions.
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    Davis, T. W.; Berry, D. L.; Boyer, G. L.; Gobler, C. J. The effects of temperature and nutrients on the growth and dynamics of toxic and non-toxic strains of microcystis during cyanobacteria blooms. Harmful Algae 2009, 8, 715– 725,  DOI: 10.1016/j.hal.2009.02.004
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    The effects of temperature and nutrients on the growth and dynamics of toxic and non-toxic strains of microcystis during cyanobacteria blooms
    Davis, Timothy W.; Berry, Dianna L.; Boyer, Gregory L.; Gobler, Christopher J.
    Harmful Algae (2009), 8 (5), 715-725CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
    In temperate latitudes, toxic cyanobacteria blooms often occur in eutrophied ecosystems during warm months. Many common bloom-forming cyanobacteria have toxic and non-toxic strains which co-occur and are visually indistinguishable but can be quantified molecularly. Toxic Microcystis cells possess a suite of microcystin synthesis genes (mcyA-mcyJ), while non-toxic strains do not. For this study, we assessed the temporal dynamics of toxic and non-toxic strains of Microcystis by quantifying the microcystin synthetase gene (mcyD) and the small subunit rRNA gene, 16S (an indicator of total Microcystis), from samples collected from four lakes across the Northeast US over a two-year period. Nutrient concns. and water quality were measured and expts. were conducted which examd. the effects of elevated levels of temps. (+4 °C), nitrogen, and phosphorus on the growth rates of toxic and non-toxic strains of Microcystis. During the study, toxic Microcystis cells comprised between 12% and 100% of the total Microcystis population in Lake Ronkonkoma, NY, and between 0.01% and 6% in three other systems. In all lakes, mol. quantification of toxic (mcyD-possessing) Microcystis was a better predictor of in situ microcystin levels than total cyanobacteria, total Microcystis, chlorophyll a, or other factors, being significantly correlated with the toxin in every lake studied. Exptl. enhanced temps. yielded significantly increased growth rates of toxic Microcystis in 83% of expts. conducted, but did so for non-toxic Microcystis in only 33% of expts., suggesting that elevated temps. yield more toxic Microcystis cells and/or cells with more mcyD copies per cell, with either scenario potentially yielding more toxic blooms. Furthermore, concurrent increases in temp. and P concns. yielded the highest growth rates of toxic Microcystis cells in most expts. suggesting that future eutrophication and climatic warming may additively promote the growth of toxic, rather than non-toxic, populations of Microcystis, leading to blooms with higher microcystin content.
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    Harke, M. J.; Gobler, C. J. Global Transcriptional responses of the toxic cyanobacterium, Microcystis aeruginosa, to nitrogen stress, phosphorus stress, and growth on organic matter. PLoS One 2013, 8, e69834  DOI: 10.1371/journal.pone.0069834
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    Global transcriptional responses of the toxic cyanobacterium, Microcystis aeruginosa, to nitrogen stress, phosphorus stress, and growth on organic matter
    Harke, Matthew J.; Gobler, Christopher J.
    PLoS One (2013), 8 (7), e69834CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Whole transcriptome shotgun sequencing (RNA-seq) was used to assess the transcriptomic response of the toxic cyanobacterium Microcystis aeruginosa during growth with low levels of dissolved inorg. nitrogen (low N), low levels of dissolved inorg. phosphorus (low P), and in the presence of high levels of high mol. wt. dissolved org. matter (HMWDOM). Under low N, one third of the genome was differentially expressed, with significant increases in transcripts obsd. among genes within the nir operon, urea transport genes (urtBCDE), and amino acid transporters while significant decreases in transcripts were obsd. in genes related to photosynthesis. There was also a significant decrease in the transcription of the microcystin synthetase gene set under low N and a significant decrease in microcystin content per Microcystis cell demonstrating that N supply influences cellular toxicity. Under low P, 27% of the genome was differentially expressed. The Pho regulon was induced leading to large increases in transcript levels of the alk. phosphatase phoX, the Pst transport system (pstABC), and the sphX gene, and transcripts of multiple sulfate transporter were also significantly more abundant. While the transcriptional response to growth on HMWDOM was smaller (5-22 % of genes differentially expressed), transcripts of multiple genes specifically assocd. with the transport and degrdn. of org. compds. were significantly more abundant within HMWDOM treatments and thus may be recruited by Microcystis to utilize these substrates. Collectively, these findings provide a comprehensive understanding of the nutritional physiol. of this toxic, bloom-forming cyanobacterium and the role of N in controlling microcystin synthesis.
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    Yu, L.; Kong, F. X.; Zhang, M.; Yang, Z.; Shi, X. L.; Du, M. Y. The dynamics of Microcystis genotypes and microcystin production and associations with environmental factors during blooms in Lake Chaohu, China. Toxins 2014, 6, 3238– 3257,  DOI: 10.3390/toxins6123238
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    The dynamics of Microcystis genotypes and microcystin production and associations with environmental factors during blooms in Lake Chaohu, China
    Yu, Li; Kong, Fanxiang; Zhang, Min; Yang, Zhen; Shi, Xiaoli; Du, Mingyong
    Toxins (2014), 6 (12), 3238-3257CODEN: TOXIB7; ISSN:2072-6651. (MDPI AG)
    Lake Chaohu, which is a large, shallow, hypertrophic freshwater lake in southeastern China, has been experiencing lake-wide toxic Microcystis blooms in recent decades. To illuminate the relationships between microcystin (MC) prodn., the genotypic compn. of the Microcystis community and environmental factors, water samples and assocd. environmental data were collected from June to Oct. 2012 within Lake Chaohu. The Microcystis genotypes and MC concns. were quantified using quant. real-time PCR (qPCR) and HPLC, resp. The results showed that the abundances of Microcystis genotypes and MC concns. varied on spatial and temporal scales. Microcystis exists as a mixed population of toxic and non-toxic genotypes, and the proportion of toxic Microcystis genotypes ranged from 9.43% to 87.98%. Both Pearson correlation and stepwise multiple regressions demonstrated that throughout the entire lake, the abundances of total and toxic Microcystis and MC concns. showed significant pos. correlation with the total phosphorus and water temp., suggesting that increases in temp. together with the phosphorus concns. may promote more frequent toxic Microcystis blooms and higher concns. of MC. Whereas, dissolved inorg. carbon (DIC) was neg. correlated with the abundances of total and toxic Microcystis and MC concns., indicating that rising DIC concns. may suppress toxic Microcystis abundance and reduce the MC concns. in the future. Therefore, our results highlight the fact that future eutrophication and global climate change can affect the dynamics of toxic Microcystis blooms and hence change the MC levels in freshwater.
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    Gobler, C. J.; Burkholder, J. M.; Davis, T. W.; Harke, M. J.; Johengen, T.; Stow, C. A.; Van de Waal, D. B. The dual role of nitrogen supply in controlling the growth and toxicity of cyanobacterial blooms. Harmful Algae 2016, 54, 87– 97,  DOI: 10.1016/j.hal.2016.01.010
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    The dual role of nitrogen supply in controlling the growth and toxicity of cyanobacterial blooms
    Gobler, Christopher J.; Burkholder, JoAnn M.; Davis, Timothy W.; Harke, Matthew J.; Johengen, Tom; Stow, Craig A.; Van de Waal, Dedmer B.
    Harmful Algae (2016), 54 (), 87-97CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
    Historically, phosphorus (P) has been considered the primary limiting nutrient for phytoplankton assemblages in freshwater ecosystems. This review, supported by new findings from Lake Erie, highlights recent mol., lab., and field evidence that the growth and toxicity of some non-diazotrophic blooms of cyanobacteria can be controlled by nitrogen (N). Cyanobacteria such as Microcystis possess physiol. adaptations that allow them to dominate low-P surface waters, and in temperate lakes, cyanobacterial densities can be controlled by N availability. Beyond total cyanobacterial biomass, N loading has been shown to selectively promote the abundance of Microcystis and Planktothrix strains capable of synthesizing microcystins over strains that do not possess this ability. Among strains of cyanobacteria capable of synthesizing the N-rich microcystins, cellular toxin quotas have been found to depend upon exogenous N supplies. Herein, multi-year observations from western Lake Erie are presented demonstrating that microcystin concns. peak in parallel with inorg. N, but not orthophosphate, concns. and are significantly lower (p < 0.01) during years of reduced inorg. nitrogen loading and concns. Collectively, this information underscores the importance of N as well as P in controlling toxic cyanobacteria blooms. Furthermore, it supports the premise that management actions to reduce P in the absence of concurrent restrictions on N loading may not effectively control the growth and/or toxicity of non-diazotrophic toxic cyanobacteria such as the cosmopolitan, toxin-producing genus, Microcystis.
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    Ecology letters (2009), 12 (12), 1326-35 ISSN:.
    The elemental composition of primary producers reflects the availability of light, carbon and nutrients in their environment. According to the carbon-nutrient balance hypothesis, this has implications for the production of secondary metabolites. To test this hypothesis, we investigated a family of toxins, known as microcystins, produced by harmful cyanobacteria. The strain Microcystis aeruginosa HUB 5-2-4, which produces several microcystin variants of different N:C stoichiometry, was cultured in chemostats supplied with various combinations of nitrate and CO(2). Excess supply of both nitrogen and carbon yielded high cellular N:C ratios accompanied by high cellular contents of total microcystin and the nitrogen-rich variant microcystin-RR. Comparable patterns were found in Microcystis-dominated lakes, where the relative microcystin-RR content increased with the seston N:C ratio. In total, our results are largely consistent with the carbon-nutrient balance hypothesis, and warn that a combination of rising CO(2) and nitrogen enrichment will affect the microcystin composition of harmful cyanobacteria.
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    Microbial Ecology (2002), 43 (4), 443-454CODEN: MCBEBU; ISSN:0095-3628. (Springer-Verlag New York Inc.)
    The growth and intracellular microcystin concn. of 2 hepatotoxic and 2 nontoxic axenic Microcystis strains were measured in batch cultures with variable nitrogen (0.84-84 mg L-1) and phosphorus (0.05-5.5 mg L-1) concns. Growth was estd. by measuring dry wt., optical d., chlorophyll a, and cellular protein concn. Microcystin concns. in cells and in culture medium were measured by HPLC anal. Both nontoxic strains needed less nutrients for their growth at low nutrient concns. With high nutrient concns., the toxic strains grew better than the nontoxic strains. Growth and intracellular microcystin concn. did not correlate in the hepatotoxic strains. Multivariate regression anal. together with math. modeling revealed a significant interactive effect of nitrogen and phosphorus, which partly explains the controversial results obtained in previous studies. In this study, it was shown that variation of nitrogen and phosphorus concns. influence the growth and the microcystin prodn. of Microcystis strains and that the strains differ in their response to nutrients. High levels of nitrogen and phosphorus in freshwaters may favor the growth of toxic Microcystis strains over nontoxic ones.
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    High accuracy, high resoln. tandem mass spectrometry (MS/MS) is becoming more common in anal. applications, yet databases of these spectra remain limited. Databases require good quality spectra with sufficient compd. information, but processing, calibration, noise redn. and retrieval of compd. information are time-consuming tasks that prevent many contributions. The authors present a comprehensive workflow for the automatic processing of MS/MS using formula annotation for recalibration and cleanup to generate high quality spectra of std. compds. for upload to MassBank (www.massbank.jp). Compd. information is retrieved via Internet services. Ref. stds. of 70 pesticides were measured at various collision energies on an LTQ-Orbitrap XL to develop and evaluate the workflow. A total of 944 resulting spectra are now available on MassBank. Evidence of N adduct formation during MS/MS fragmentation processes was found, highlighting the benefits high accuracy MS/MS offers for spectral interpretation. A database of recalibrated, cleaned-up spectra resulted in the most correct spectra ranked in 1st place, regardless of whether the search spectra were recalibrated or not, whereas the av. rank of the correct mol. formula was improved from 2.55 (uncalibrated) to 1.53 when using recalibrated MS/MS data. The workflow is available as an R package RMassBank capable of generating MassBank records from raw MS and MS/MS data and can be adjusted to process data acquired with different settings and instruments. This workflow is a vital step towards addressing the need for more high quality, high accuracy MS/MS spectra in spectral databases and provides important information for spectral interpretation. Copyright © 2012 John Wiley and Sons, Ltd.
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    Journal of Antibiotics (1993), 46 (10), 1550-6CODEN: JANTAJ; ISSN:0021-8820.
    Four depsipeptides (peptide lactones), called cyanopeptolins A, B, C and D, have been isolated from the cyanobacterium Microcystis sp. PCC 7806. They possess identical structures consisting of cyclic L-glutamic acid-γ-aldehyde, L-leucine, N-methyl-phenylalanine, L-valine, L-threonine, L-aspartic acid, hexanoic acid and a variable basic amino acid. This variable amino acid can be L-arginine (cyanopeptolin A), L-lysine (cyanopeptolin B), Nε-methyl-L-lysine (cyanopeptolin C) and Nε,Nε-dimethyl-L-lysine (cyanopeptolin D), resp. The L-glutamic acid-γ-aldehyde and the amino group of L-leucine form an unusual 3-amino-6-hydroxy-2-oxo-1-piperidine system. L-Threonine is connected to L-valine via its hydroxy-group forming an ester bonding. The hexanoic acid residue is attached to the N-terminal aspartic acid residue which is not a part of the ring structure. The isolation procedure of the four cyanopeptolins as well as structure elucidation are described. Amino acid anal., GC/MS anal., FAB-MS and several NMR techniques were used to reveal the structures.
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    Journal of Natural Products (2004), 67 (10), 1755-1757CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
    A new depsipeptide, cyanopeptolin 963 A (I), was isolated from an axenic strain of the toxic freshwater cyanobacterium Microcystis PCC 7806. The structure of this compd. was elucidated by chem. and spectroscopic analyses, including high-resoln. ESI-FTICR-MS, 2-D NMR, and GC-MS of the hydrolyzate. The major structural difference compared to previously characterized cyanopeptolins of this strain is the replacement of the basic amino acid in position 3 by L-tyrosine. I displayed inhibitory activity against chymotrypsin with an IC50 value of 0.9 μM.
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    Hepatotoxin production in cyanobacteria has been shown to correlate to external stimuli such as light and nutrient concentrations and ratios, although conflicting results have been reported. Specific growth rates and protein and microcystin content of M. aeruginosa PCC7806 and M. aeruginosa UV027 were determined under nonlimiting batch culture conditions for a range of medium nitrogen and phosphorous atomic ratios. Both strains exhibited a similar optimal medium N:P ratio for increased cellular microcystin levels. Additionally, total cellular protein content and intracellular microcystin content were significantly correlated to each other (r2 = 0.81, p < 0.001). Microcystin and protein content increased considerably as the maximum specific growth rate for the experimental conditions was reached. The significant correlation of cellular protein and microcystin content and their relative increase with increasing specific growth rate, within defined ranges of medium N:P ratios, suggest a close association between microcystin production and N:P ratio-dependent assimilation of nitrogen, and resulting total cellular protein levels, which may be further modulated by specific growth rate.
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    Isolation of aerucyclamides C and D and structure revision of microcyclamide 7806A: Heterocyclic ribosomal peptides from Microcystis aeruginosa PCC 7806 and their antiparasite evaluation
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    Journal of Natural Products (2008), 71 (11), 1891-1896CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    Aerucyclamides C and D were isolated from the cyanobacterium Microcystis aeruginosa PCC 7806, and their structures were established by NMR spectroscopy and chem. transformation and degrdn. Acidic hydrolysis of aerucyclamide C (CF3CO2H, H2O) resulted in microcyclamide 7806A. This chem. evidence combined with spectroscopic and phys. data suggest a structure revision for microcyclamide 7806A, which incorporates an O-acylated Thr ammonium residue instead of the originally proposed Me oxazoline ring. The authors have prepd. microcyclamide 7806B upon basic and acidic treatment of microcyclamide 7806A, which suggests that both these compds. are hydrolysis products of aerucyclamide C and that the aerucyclamides A-D are the actual metabolites produced via ribosomal peptide synthesis in M. aeruginosa PCC 7806. Antiplasmodial evaluation established submicromolar IC50 values for aerucyclamide B against Plasmodium falciparum; low micromolar values for aerucyclamide C were found against Trypanosoma brucei rhodesiense. The compds. were selective for the parasites over a cell line of L6 rat myoblasts and are thus considered for further study as antimalarial agents.
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    The structures of the hepatotoxins of general name cyanoginosins-XY are proposed to be cyclo-D-Ala-L-X-erythro-β-methyl-D-isoAsp-L-Y-Adda-D-isoGlu-N-methyldehydroAla, were X and Y represent variable amino acids and Adda is 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid. The structural studies on 4 variant toxins utilized NMR and mass spectral methods analogous to those recently used to det. the structure of cyanoginosin-LA.
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    Phytochemistry (1997), 44 (3), 449-452CODEN: PYTCAS; ISSN:0031-9422. (Elsevier)
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    First evidence of MC-HtyR associated to a Plankthothrix rubescens blooming in an Italian lake based on a LC-MS method for routinely analysis of twelve microcystins in freshwaters
    Di Gregorio, F. Nigro; Bogialli, S.; Ferretti, E.; Lucentini, L.
    Microchemical Journal (2017), 130 (), 329-335CODEN: MICJAN; ISSN:0026-265X. (Elsevier B.V.)
    A recent Italian regulatory level for microcystins (MCs) in drinking water was set at 1.0 μg/L, intended as the sum of all variants that can be detd. using com. available stds. A selective multi-residue method for analyzing twelve variants of MCs (MC-RR, MC-YR, MC-LR, MC-LA, MC-LW, MC-LF, MC-LY, [D-Asp3]-MC-RR, [D-Asp3]-MC-LR, MC-WR, MC-HilR, MC-HtyR) in surface and drinking waters was optimized and validated in accordance with the Italian implementation of the Drinking Water Directive 98/83/EC. The proposed method was robust as proved by using nodularin as quality control, with inter-matrixes reproducibility better than 17% and matrix effects not significantly dependent among different water samples. LODs were in the range of 0.003-0.030 μg/L for all the analytes, allowing the quant. anal. of selected MCs at levels lower than 1/10 of the proposed new Italian parametric values. The method was tailored for the routine anal. of MCs in the frame of risk management related to MCs prodn. during toxic algal blooms. The optimized anal. protocol was then applied to the anal. of water samples collected in Occhito Lake (Apulia, Italy), used as a source of drinking water, after an extraordinary bloom of Planktothrix rubescens. In Oct. 2010, the presence of MC-HtyR was detected here with max. concn. level of 0.025 μg/L. To our knowledge, this is the first report on MC-HtyR presence, obtained with a confirmatory method, assocd. to a P. rubescens bloom in surface waters.
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    Sano, T.; Beattie, K. A.; Codd, G. A.; Kaya, K. Two (Z)-dehydrobutyrine-containing microcystins from a hepatotoxic bloom of Oscillatoria agardhii from Soulseat Loch, Scotland. J. Nat. Prod. 1998, 61, 851– 853,  DOI: 10.1021/np980047m
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    Two (Z)-dehydrobutyrine-containing microcystins from a hepatotoxic bloom of Oscillatoria agardhii from Soulseat Loch, Scotland
    Sano, Tomoharu; Beattie, Kenneth A.; Codd, Geoffrey A.; Kaya, Kunimitsu
    Journal of Natural Products (1998), 61 (6), 851-853CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
    Two (Z)-dehydrobutyrine (Dhb)-contg. microcystins, [D-Asp3,(Z)-Dhb7]microcystin-HtyR (I) and [D-Asp3,(Z)-Dhb7]microcystin-LR (II), were isolated from a hepatotoxic bloom of the cyanobacterium Oscillatoria agardhii from a freshwater lake in Scotland. The geometrical structure of the Dhb units in the microcystins was detd. as Z on the basis of NOE and ROESY expts.
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    Rapala, J.; Sivonen, K.; Lyra, C.; Niemela, S. I. Variation of microcystins, cyanobacterial hepatotoxins, in Anabaena spp. as a function of growth stimuli. Appl. Environ. Microbiol. 1997, 63, 2206– 2212,  DOI: 10.1128/AEM.63.6.2206-2212.1997
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    Variation of microcystins, cyanobacterial hepatotoxins, in Anabaena spp. as a function of growth stimuli
    Rapala, Jarkko; Sivonen, Kaarina; Lyra, Christina; Niemela, Seppo I.
    Applied and Environmental Microbiology (1997), 63 (6), 2206-2212CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
    Cyanobacterial hepatotoxins, microcystins, are specific inhibitors of serine/threonine protein phosphatases and potent tumor promoters. They have caused several poisonings of animals and also pose a health hazard for humans through the use of water for drinking and recreation. Different strains of the same cyanobacterial species may variously be nontoxic, be neurotoxic, or produce several microcystin variants. It is poorly understood how the amt. of toxins varies in a single strain. This lab. study shows the importance of external growth stimuli in regulating the levels and relative proportions of different microcystin variants in 2 strains of filamentous, N2-fixing Anabaena spp. The concn. of the toxins in the cells increased with P. High temps. (25-30°), together with the highest levels of light studied (test range, 2-100 μmol/m2-s), decreased their amt. Different structural variants of microcystins responded differently to growth stimuli. Variants of microcystin (MCYST)-LR correlated with temps. <25° and those of MCYST-RR correlated with higher temps. N added to the growth medium and increasing temps. increased the proportion of microcystin variants demethylated in amino acid 3. All variants remained mostly intracellular. Time was the most important factor causing the release of the toxins into the growth medium. Time, N added to the growth medium, and light fluxes >25 μmol/m2-s significantly increased the concns. of dissolved toxins. It thus seems that the redn. of P loads in bodies of water might play a role in preventing the health hazards that toxic cyanobacterial water blooms pose, not only by decreasing the cyanobacteria but also by decreasing their toxin content.
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    Wiedner, C.; Visser, P. M.; Fastner, J.; Metcalf, J. S.; Codd, G. A.; Mur, L. R. Effects of light on the microcystin content of Microcystis strain PCC 7806. Appl. Environ. Microbiol. 2003, 69, 1475– 1481,  DOI: 10.1128/AEM.69.3.1475-1481.2003
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    Effects of light on the microcystin content of Microcystis strain PCC 7806
    Wiedner, Claudia; Visser, Petra M.; Fastner, Jutta; Metcalf, James S.; Codd, Geoffrey A.; Mur, Luuc R.
    Applied and Environmental Microbiology (2003), 69 (3), 1475-1481CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
    Many cyanobacteria produce microcystins, hepatotoxic cyclic heptapeptides that can affect animals and humans. The effects of photosynthetically active radiation (PAR) on microcystin prodn. by Microcystis strain PCC 7806 were studied in continuous cultures. Microcystis strain PCC 7806 was grown under PAR intensities between 10 and 403 μmol of photons m-2 s-1 on a light-dark rhythm of 12 h-12 h. The microcystin concn. per cell, per unit biovolume and protein, was estd. under steady-state and transient-state conditions and on a diurnal timescale. The cellular microcystin content varied between 34.5 and 81.4 fg cell-1 and was significantly pos. correlated with growth rate under PAR-limited growth but not under PAR-satd. growth. Microcystin prodn. and PAR showed a significant pos. correlation under PAR-limited growth and a significant neg. correlation under PAR-satd. growth. The microcystin concn., as a ratio with respect to biovolume and protein, correlated neither with growth rate nor with PAR. Adaptation of microcystin prodn. to a higher irradiance during transient states lasted for 5 days. During the period of illumination at a PAR of 10 and 40 μmol of photons m-2 s-1, the intracellular microcystin content increased to values 10 to 20% higher than those at the end of the dark period. Extracellular (dissolved) microcystin concns. were 20 times higher at 40 μmol of photons m-2 s-1, than at 10 μmol of photons m-2 s-1 and did not change significantly during the light-dark cycles at both irradiances. In summary, our results showed a pos. effect of PAR on microcystin prodn. and content of Microcystis strain PCC 7806 up to the point where the max. growth rate is reached, while at higher irradiances the microcystin prodn. is inhibited.
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    Saxton, M. A.; Arnold, R.; Bourbonniere, R. A.; McKay, R. M. L.; Wilhelm, S. W. Plasticity of total and intracellular phosphorus quotas in Microcystis aeruginosa cultures and Lake Erie algal assemblages. Front. Microbiol. 2012, 3, 3  DOI: 10.3389/fmicb.2012.00003
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    Plasticity of total and intracellular phosphorus quotas in Microcystis aeruginosa cultures and Lake Erie algal assemblages
    Saxton, Matthew A.; Arnold, Robert J.; Bourbonniere, Richard A.; McKay, Robert Michael L.; Wilhelm, Steven W.
    Frontiers in Aquatic Microbiology (2012), 3 (Jan.), 3CODEN: FAMRCY ISSN:. (Frontiers Media S.A.)
    Blooms of the potentially toxic cyanobacterium Microcystis are common events globally, and as a result significant resources continue to be dedicated to monitoring and controlling these events. Recent studies have shown that a significant proportion of total cell-assocd. phosphorus (P) in marine phytoplankton can be surface adsorbed; as a result studies completed to date do not accurately report the P demands of these organisms. In this study, we measure the total cell-assocd. and intracellular P as well as growth rates of two toxic strains of Microcystis aeruginosa Kutz grown under a range of P concns. The results show that the intracellular P pool in Microcystis represents a percentage of total cell-assocd. P (50-90 %) similar to what has been reported for actively growing algae in marine systems. Intracellular P concns. (39-147 fg cell-1) generally increased with increasing P concns. in the growth medium, but growth rate and the ratio of total cell-assocd. to intracellular P remained generally stable. Intracellular P quotas and growth rates in cells grown under the different P treatments illustrate the ability of this organism to successfully respond to changes in ambient P loads, and thus have implications for ecosystem scale productivity models employing P concns. to predict algal bloom events.
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    Kuniyoshi, T. M.; Sevilla, E.; Bes, M. T.; Fillat, M. F.; Peleato, M. L. Phosphate deficiency (N/P 40:1) induces mcyD transcription and microcystin synthesis in Microcystis aeruginosa PCC7806. Plant Physiol. Biochem. 2013, 65, 120– 124,  DOI: 10.1016/j.plaphy.2013.01.011
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    Phosphate deficiency (N/P 40:1) induces mcyD transcription and microcystin synthesis in Microcystis aeruginosa PCC7806
    Kuniyoshi, Tais M.; Sevilla, Emma; Bes, M. Teresa; Fillat, Maria F.; Peleato, M. Luisa
    Plant Physiology and Biochemistry (Issy-les-Moulineaux, France) (2013), 65 (), 120-124CODEN: PPBIEX; ISSN:0981-9428. (Elsevier Masson SAS)
    A real-time RT-PCR anal. of the transcriptional response to phosphate availability of the mcyD gene and microcystin-LR synthesis in Microcystis aeruginosa PCC7806 revealed that no significant changes were obsd. in the relative quantification of mcyD under excess phosphate (N/P = 1:1), whereas in deficiency of this nutrient (N/P = 40:1), a steady increase of mcyD during the exponential growth phase was detected, showing a maximal level on the 7th day of growth with a 6.8-fold increase over the control cells. The microcystin content in phosphate deficient cells correlates with the trend of mcyD transcription obsd. Also, the authors demonstrate that under phosphate deficiency conditions with a ratio of 40:1 N/P, the growth of M. aeruginosa PCC7806 was not affected when compared to control and phosphate excess samples. When blooms occur, the nutrients become exhausted and therefore phosphate availability will be scarce. In such a complex scenario, microcystin synthesis could be a response to phosphate deficiency, among other stress parameters.
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    Jankowiak, J.; Hattenrath-Lehmann, T.; Kramer, B. J.; Ladds, M.; Gobler, C. J. Deciphering the effects of nitrogen, phosphorus, and temperature on cyanobacterial bloom intensification, diversity, and toxicity in western Lake Erie. Limnol. Oceanogr. 2019, 64, 1347– 1370,  DOI: 10.1002/lno.11120
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    Deciphering the effects of nitrogen, phosphorus, and temperature on cyanobacterial bloom intensification, diversity, and toxicity in western Lake Erie
    Jankowiak, Jennifer; Hattenrath-Lehmann, Theresa; Kramer, Benjamin J.; Ladds, Megan; Gobler, Christopher J.
    Limnology and Oceanography (2019), 64 (3), 1347-1370CODEN: LIOCAH; ISSN:0024-3590. (John Wiley & Sons, Inc.)
    Although cyanobacterial harmful algal blooms (CHABs) are promoted by nutrient loading and elevated temps., the effects of these processes on bloom diversity are unclear. This study used traditional and next-generation sequencing approaches to assess shifts in phytoplankton, cyanobacterial (16S rRNA), and microcystin-producing (mcyE) communities during CHABs in western Lake Erie (Maumee and Sandusky Bays) in response to natural and exptl. gradients of nitrogen (N), phosphorus (P), and temp. CHABs were most intense near the Maumee and Sandusky Rivers and were dominated by Microcystis and Planktothrix, resp. Sequencing of 16S amplicons revealed cryptic cyanobacterial diversity (47 genera) including high abundances of two distinct clades of Synechococcus in both bays and significant differences in community structure between nutrient-rich nearshore sites and less eutrophic offshore sites. Sequencing of mcyE genes revealed low taxonomic (n = 3) but high genetic diversity (n = 807), with toxigenic strains of Planktothrix being more abundant than Microcystis and more closely paralleling microcystin concns. Cyanobacterial abundance significantly increased in response to elevated N, with the greatest increases in combined high N, P, and temp. treatments that concurrently suppressed green and brown algae. N significantly increased microcystin concns. and the relative abundance of nondiazotrophic genera such as Planktothrix, while diazotrophic genera such as Dolichospermum and Aphanizomenon were, in some cases, enhanced by high P and temp. While nutrients and elevated temps. promote CHABs, differing combinations selectively promote individual cyanobacterial genera and strains, indicating management of both N and P will be required to control all cyanobacteria in Lake Erie, particularly as lake temps. rise.
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    Harke, M. J.; Davis, T. W.; Watson, S. B.; Gobler, C. J. Nutrient-controlled niche differentiation of western Lake Erie cyanobacterial populations revealed via metatranscriptomic surveys. Environ. Sci. Technol. 2016, 50, 604– 615,  DOI: 10.1021/acs.est.5b03931
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    Nutrient-Controlled Niche Differentiation of Western Lake Erie Cyanobacterial Populations Revealed via Metatranscriptomic Surveys
    Harke, Matthew J.; Davis, Timothy W.; Watson, Susan B.; Gobler, Christopher J.
    Environmental Science & Technology (2016), 50 (2), 604-615CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    Although toxic cyanobacterial blooms in western Lake Erie threaten drinking water supplies and are promoted by nutrient loading, the precise nutrient regime that selects specific cyanobacteria populations is poorly understood. We assess shifts in cyanobacterial abundances and global gene-expression patterns in response to natural and manipulated gradients in N and P to identify gene pathways that facilitate dominance by different cyanobacteria. Gradients in sol. reactive phosphorus shaped cyanobacterial communities and elicited the largest transcriptomic responses. Under high-P conditions (closest to the mouth of the Maumee River), Anabaena and Planktothrix were the dominant cyanobacterial populations, and exptl. P and ammonium enrichment promoted N fixation gene (nifH) expression in Anabaena. For Microcystis, exptl. addns. of P up-regulated genes involved in phage defense, genomic rearrangement, and nitrogen acquisition but led to lower abundances. Within offshore, low-P regions of the western basin of Lake Erie, Microcystis up-regulated genes assocd. with P scavenging (pstSCAB, phoX) and dominated cyanobacterial communities. Exptl. addns. of ammonium and urea did not alter Microcystis abundances but did up-regulate protease inhibitors (aer and mcn gene sets) and microcystin synthetase genes (mcy), with urea enrichment yielding significant increases in microcystin concns. Our findings suggest that management plans that reduce P loads alone may not significantly reduce the risk of cyanobacterial blooms in western Lake Erie but rather may promote a shift among cyanobacterial populations (Microcystis, Anabaena, and Planktothrix) toward a greater dominance by toxic strains of Microcystis.
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    Wan, L. L.; Chen, X. Y.; Deng, Q. H.; Yang, L.; Li, X. W.; Zhang, J. Y.; Song, C. L.; Zhou, Y. Y.; Cao, X. Y. Phosphorus strategy in bloom-forming cyanobacteria (Dolichospermum and Microcystis) and its role in their succession. Harmful Algae 2019, 84, 46– 55,  DOI: 10.1016/j.hal.2019.02.007
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    Phosphorus strategy in bloom-forming cyanobacteria (Dolichospermum and Microcystis) and its role in their succession
    Wan, Lingling; Chen, Xiaoyan; Deng, Qinghui; Yang, Liu; Li, Xiaowen; Zhang, Junyi; Song, Chunlei; Zhou, Yiyong; Cao, Xiuyun
    Harmful Algae (2019), 84 (), 46-55CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
    Dolichospermum (formerly Anabaena) and Microcystis cause harmful cyanobacterial blooms in freshwater ecosystems worldwide. Input redn. of both nitrogen (N) and phosphorus (P) are commonly recognized as basic ways of controlling blooms, but little is known about the roles of nutrients and their using strategy among cyanobacteria in triggering the succession of diazotrophic to non-diazotrophic cyanobacteria. In this study, we investigated in situ responses of cyanobactria to ambient P status during the transition from Dolichospermum flos-aquae to Microcystis spp. in Lake Taihu and Lake Chaohu. While dominant in phytoplankton community, D. flos-aquae experienced P deficiency as evidenced by qual. detection of extracellular phosphatase via enzyme labeled fluorescence (ELF). The percentage of ELF-labeled D. flos-aquae cells was 33% when it dominated the phytoplankton community, and was 78% when it co-dominated with Microcystis spp., indicating an increase in P deficiency. Meanwhile, no ELF-labeled Microcystis cells were obsd. while polyphosphate body (PPB) were present, suggesting that Microcystis spp. were not P deficient. Addnl., the percentages of Microcystis cells contg. PPB showed an inverted "U-shaped" relationship with concns. on sol. reactive phosphorus (SRP). To validate the field observation, a lab. study of the monocultures of the dominant cyanobacteria was conducted. Extracellular alk. phosphatase activity (APA) and PPB accumulation were regulated by P availability in monocultures of D. flos-aquae. Interestingly, no cell bound extracellular phosphatase was found on Microcystis aeruginasa even in the culture without P supply. Consistently, the expressions of phosphatase encoding gene phoX showed no differences among the treatments. The way in which PPB accumulation occurred in Microcystis spp. in response to P availability in the cultures was similar to that obsd. in the field, demonstrating a strategy of energy conservation over P accumulation. The competitive advantage of Microcystis spp. was displayed at low P concns.: where it could rapidly uptake and store inorg. P, which also increased the P deficiency of the coexisting phytoplankton species. Responses of P-transport gene pstS confirmed this hypothesis. The physiol. and mol. mechanisms mentioned above enable Microcystis to survive and proliferate in environment with low available P supply more efficiently. In conclusion, different cyanobacterial species have distinct ways of responding to P availability, suggesting that the control of cyanobacterial blooms by targeted nutrient redn. is largely dependent upon the dominant species. P redn. is more effective in controlling diazotrophic cyanobacteria than non-diazotrophic cyanobacteria.
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    Facey, J. A.; Apte, S. C.; Mitrovic, S. M. A Review of the effect of trace metals on freshwater cyanobacterial growth and toxin production. Toxins 2019, 11, 643  DOI: 10.3390/toxins11110643
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    Long, B. M.; Jones, G. J.; Orr, P. T. Cellular microcystin content in N-limited Microcystis aeruginosa can be predicted from growth rate. Appl. Environ. Microbiol. 2001, 67, 278– 283,  DOI: 10.1128/AEM.67.1.278-283.2001
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    Cellular microcystin content in N-limited Microcystis aeruginosa can be predicted from growth rate
    Long, Benedict M.; Jones, Gary J.; Orr, Philip T.
    Applied and Environmental Microbiology (2001), 67 (1), 278-283CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
    Cell quotas of microcystin (QMCYST; femtomoles of MCYST per cell), protein, and chlorophyll a (Chl a), cell dry wt., and cell vol. were measured over a range of growth rates in N-limited chemostat cultures of the toxic cyanobacterium Microcystis aeruginosa MASH 01-A19. There was a pos. linear relationship between QMCYST and specific growth rate (μ), from which we propose a generalized model that enables QMCYST at any nutrient-limited growth rate to be predicted based on a single batch culture expt. The model predicts QMCYST from μ, μmax (max. specific growth rate), QMCYSTmax (max. cell quota), and QMCYSTmin (min. cell quota). Under the conditions examd. in this study, we predict a QMCYSTmax of 0.129 fmol cell-1 at μmax and a QMCYSTmin of 0.050 fmol cell-1 at μ = 0. Net MCYST prodn. rate (RMCYST) asymptotes to zero at μ = 0 and reaches a max. of 0.155 fmol cell-1 day-1 at μmax. MCYST/dry wt. ratio (milligrams per g [dry wt.]) increased linearly with μ, whereas the MCYST/protein ratio reached a max. at intermediate μ. In contrast, the MCYST/Chl a ratio remained const. Cell vol. correlated neg. with μ, leading to an increase in intracellular MCYST concn. at high μ. Taken together, our results show that fast-growing cells of N-limited M. aeruginosa are smaller, are of lower mass, and have a higher intracellular MCYST quota and concn. than slow-growing cells. The data also highlight the importance of detg. cell MCYST quotas, as potentially confusing interpretations can arise from detg. MCYST content as a ratio to other cell components.
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    Horst, G. P.; Sarnelle, O.; White, J. D.; Hamilton, S. K.; Kaul, R. B.; Bressie, J. D. Nitrogen availability increases the toxin quota of a harmful cyanobacterium, Microcystis aeruginosa. Water Res. 2014, 54, 188– 198,  DOI: 10.1016/j.watres.2014.01.063
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    Nitrogen availability increases the toxin quota of a harmful cyanobacterium, Microcystis aeruginosa
    Horst, Geoffrey P.; Sarnelle, Orlando; White, Jeffrey D.; Hamilton, Stephen K.; Kaul, Raj Reni B.; Bressie, Julianne D.
    Water Research (2014), 54 (), 188-198CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
    An important objective in understanding harmful phytoplankton blooms is detg. how environmental factors influence the toxicity of bloom-forming species. We examd. how nutrients and grazers (dreissenid mussels) affect the prodn. of microcystin (a liver toxin) by the cyanobacterium Microcystis aeruginosa, via a combination of field and lab. expts., and field observations in Lake Erie. The field expt. revealed no effect of mussel d. on microcystin quota (particulate microcystin per unit Microcystis biomass). In contrast, in both field and lab. expts., nitrogen-limited conditions led to substantially reduced microcystin quota relative to phosphorus-limited or nutrient-satd. conditions. In the field expt., microcystin per unit of mcyB gene was strongly reduced under nitrogen-limited conditions, indicating a phenotypic response. Results from a seasonal survey in the western basin of Lake Erie revealed a similar neg. influence of nitrogen limitation (as indexed by nitrate concn.) on microcystin quota. Our results are consistent with stoichiometric considerations in that the cell quota of a nitrogen-rich secondary metabolite, microcystin, was reduced disproportionately under nitrogen limitation.
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    Tillett, D.; Dittmann, E.; Erhard, M.; von Döhren, H.; Borner, T.; Neilan, B. A. Structural organization of microcystin biosynthesis in Microcystis aeruginosa PCC7806: an integrated peptide-polyketide synthetase system. Chem. Biol. 2000, 7, 753– 764,  DOI: 10.1016/S1074-5521(00)00021-1
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    Structural organization of microcystin biosynthesis in Microcystis aeruginosa PCC7806: an integrated peptide-polyketide synthetase system
    Tillett, Daniel; Dittmann, Elke; Erhard, Marcel; Von Dohren, Hans; Borner, Thomas; Neilan, Brett A.
    Chemistry & Biology (2000), 7 (10), 753-764CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Science Ltd.)
    Blooms of toxic cyanobacteria (blue-green algae) have become increasingly common in the surface waters of the world. Of the known toxins produced by cyanobacteria, the microcystins are the most significant threat to human and animal health. These cyclic peptides are potent inhibitors of eukaryotic protein phosphatases type 1 and 2A. Synthesized nonribosomally, the microcystins contain a no. of unusual amino acid residues including the β-amino polyketide moiety Adda (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoic acid). We have characterized the microcystin biosynthetic gene cluster from Microcystis aeruginosa PCC7806. A cluster spanning 55 kb, composed of 10 bidirectionally transcribed open reading frames arranged in two putative operons (mcyA-C and mcyD-J), has been correlated with microcystin formation by gene disruption and mutant anal. Of the 48 sequential catalytic reactions involved in microcystin synthesis, 45 have been assigned to catalytic domains within six large multienzyme synthases/synthetases (McyA-E, G), which incorporate the precursors phenylacetate, malonyl-CoA, S-adenosyl-L-methionine, glutamate, serine, alanine, leucine, D-methyl-isoaspartate, and arginine. The addnl. four monofunctional proteins are putatively involved in O-methylation (McyJ), epimerization (McyF), dehydration (Mcyl), and localization (McyH). The unusual polyketide amino acid Adda is formed by transamination of a polyketide precursor as enzyme-bound intermediate, and not released during the process. This report is the first complete description of the biosynthesis pathway of a complex cyanobacterial metabolite. The enzymic organization of the microcystin assembly represents an integrated polyketide-peptide biosynthetic pathway with a no. of unusual structural and enzymic features. These include the integrated synthesis of a β-amino-pentaketide precursor and the formation of β- and γ-carboxyl-peptide bonds, resp. Other features of this complex system also obsd. in diverse related biosynthetic clusters are integrated C- and N-methyltransferases, an integrated aminotransferase, and an assocd. O-methyltransferase and a racemase acting on acidic amino acids.
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  • Abstract

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    Figure 1

    Figure 1. (A) Growth curves of M. aeruginosa as log-normalized cell abundance (log Ct/C0) for batch experiments in a medium with 1 mmol L–1 nitrogen and at three total phosphorous concentrations being 0.50 mmol L–1 (N/P = 2), 0.05 mmol L–1 (N/P = 20), and 0.025 mmol L–1 (N/P = 40). The growth parameters μ being the exponential growth rate per day and λ being the lag time before exponential growth in days were obtained by fitting to the Richard model and are listed in the insert. (B) Total cyanopeptide concentrations in nmol mL–1 cyanopeptide class equivalence relative to total cell abundance. The slope represents the cyanopeptide production rate in fmol per cell and parameters of the linear regression are listed in the insert.

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    Figure 2

    Figure 2. Cyanopeptide concentration per cell in class equivalents over the growth curve for M. aeruginosa for the total production of cyanopeptides (A) and by cyanopeptide class of cyclamides (B), microcystins (C), and cyanopeptolins (D). The shown chemical structures are representative compounds for each cyanopeptide class: aerucyclamide A, microcystin-LR, and cyanopeptolin A, but the shown concentration values represent the sum of all identified members for each class.

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    Figure 3

    Figure 3. Fitted growth curves of (A) M. aeruginosa and (B) D. flos-aquae as log-normalized cell abundance (log Ct/C0) for batch experiments in modified WC medium at six different nutrient concentrations, including the reference conditions with 1 mmol N L–1 and 0.05 mmol P L–1 (control, black), 3-fold increase of P (+P, purple), 100-fold decrease of P (−P, blue), 100-fold decrease of N (−N, green), 100-fold decrease of P and N (−N and −P, orange), and 100-fold decrease of micronutrients (−MN, red). The growth parameters obtained by fitting the Richard model are indicated with μ being the exponential growth rate per day and λ being the lag time before exponential growth in days.

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    Figure 4

    Figure 4. Total cyanopeptide concentration in nmol class equivalent per dry weight for (A) M. aeruginosa PCC7806 and (B) D. flos-aquae under six different nutrient conditions, including the reference conditions with 1 mmol N L–1 and 0.05 mmol P L–1 and enhanced total phosphorous (+P, by factor 3), reduced total phosphorous (−P, by factor 100), reduced total nitrogen (−N, by factor 100), reduced total phosphorous and nitrogen (both −N and −P by factor 100), and reduced micronutrient concentration (−MN by factor 100) relative to the control conditions (WC medium). The pie charts represent the cyanopeptide profile with relative contribution of cyclamides (blue), cyanopeptolins (green), microcystins (yellow), and anabaenopeptins (purple). p-Values of t-test from comparison to the control conditions are listed. *p-Value < 0.1 and **p-value < 0.05.

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  • References

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    This article references 68 other publications.

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      Toxin prodn. by harmful cyanobacteria blooms (CyanoHABs) constitutes a major, worldwide environmental threat to freshwater aquatic resources that is expected to expand in scale and intensity with global climate change. Extensive literature exists on the most frequently encountered cyanotoxin, microcystin, in freshwater environments. Yet, the expansion of microcystin producing CyanoHABs and the transport of contaminated inland waters to estuarine and coastal marine waters has only recently received attention. This paper synthesizes information on the salinity tolerance of microcystin producing cyanobacteria and summarizes available case reports on microcystin presence in estuarine and coastal waters. We highlight a potential food-borne exposure route to humans by reviewing the growing body of evidence that shows microcystins can accumulate in coastal seafood. These cases reinforce the importance of freshwater nutrient redn. and the need for freshwater management efforts to look beyond lacustrine and riverine systems. Events reviewed here likely only represent a small proportion of cases where microcystins affect estuarine and coastal waters. We strongly suggest increased monitoring and research efforts to understand, react to, and prevent ecol. and health problems assocd. with the growing problem of toxic CyanoHABs in coastal environments.
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      Backer Lorraine C; Landsberg Jan H; Miller Melissa; Keel Kevin; Taylor Tegwin K
      Toxins (2013), 5 (9), 1597-628 ISSN:.
      Cyanobacteria (also called blue-green algae) are ubiquitous in aquatic environments. Some species produce potent toxins that can sicken or kill people, domestic animals, and wildlife. Dogs are particularly vulnerable to cyanotoxin poisoning because of their tendency to swim in and drink contaminated water during algal blooms or to ingestalgal mats.. Here, we summarize reports of suspected or confirmed canine cyanotoxin poisonings in the U.S. from three sources: (1) The Harmful Algal Bloom-related Illness Surveillance System (HABISS) of the National Center for Environmental Health (NCEH), Centers for Disease Control and Prevention (CDC); (2) Retrospective case files from a large, regional veterinary hospital in California; and (3) Publicly available scientific and medical manuscripts; written media; and web-based reports from pet owners, veterinarians, and other individuals. We identified 231 discreet cyanobacteria harmful algal bloom (cyanoHAB) events and 368 cases of cyanotoxin poisoning associated with dogs throughout the U.S. between the late 1920s and 2012. The canine cyanotoxin poisoning events reviewed here likely represent a small fraction of cases that occur throughout the U.S. each year.
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    8. 8
      Ibelings, B. W.; Backer, L. C.; Kardinaal, W. E. A.; Chorus, I. Current approaches to cyanotoxin risk assessment and risk management around the globe. Harmful Algae 2014, 40, 63– 74,  DOI: 10.1016/j.hal.2014.10.002
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      8
      Current approaches to cyanotoxin risk assessment and risk management around the globe
      Ibelings, Bas W.; Backer, Lorraine C.; Kardinaal, W. Edwin A.; Chorus, Ingrid
      Harmful Algae (2014), 40 (), 63-74CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
      Toxic cyanobacteria became more widely recognized as a potential health hazard in the 1990s, and in 1998 the World Health Organization (WHO) first published a provisional Guideline Value of 1 μg L-1 for microcystin-LR in drinking-water. In this publication, we compare risk assessment and risk management of toxic cyanobacteria in 17 countries across all five continents. We focus on the three main (oral) exposure vehicles to cyanotoxins: drinking-water, water related recreational and freshwater seafood. Most countries have implemented the provisional WHO Guideline Value, some as legally binding std., to ensure the distribution of safe drinking-water with respect to microcystins. Regulation, however, also needs to address the possible presence of a wide range of other cyanotoxins and bioactive compds., for which no guideline values can be derived due to insufficient toxicol. data. The presence of microcystins (commonly expressed as microcystin-LR equiv.) may be used as proxy for overall guidance on risk management, but this simplification may miss certain risks, for instance from dissolved fractions of cylindrospermopsin and cyanobacterial neurotoxins. An alternative approach, often taken for risk assessment and management in recreational waters, is to regulate cyanobacterial presence - as cell nos. or biomass - rather than individual toxins. Here, many countries have implemented a two or three tier alert level system with incremental severity. These systems define the levels where responses are switched from Surveillance to Alert and finally to Action Mode and they specify the short-term actions that follow. Surface bloom formation is commonly judged to be a significant risk because of the elevated concn. of microcystins in a scum. Countries have based their derivations of legally binding stds., guideline values, maximally allowed concns. (or limits named otherwise) on very similar scientific methodol., but underlying assumptions such as bloom duration, av. body size and the amt. of water consumed while swimming vary according to local circumstances. Furthermore, for toxins with incomplete toxicol. data elements of expert judgment become more relevant and this also leads to a larger degree of variation between countries' thresholds triggering certain actions. Cyanobacterial blooms and their cyanotoxin content are a highly variable phenomenon, largely depending on local conditions, and likely concns. can be assessed and managed best if the specific conditions of the locality are known and their impact on bloom occurrence are understood. Risk Management Frameworks, such as for example the Water Safety Plan concept of the WHO and the 'bathing water profile' of the European Union are suggested to be effective approaches for preventing human exposure by managing toxic cyanobacteria from catchment to consumer for drinking water and at recreational sites.
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    9. 9
      Welker, M.; Brunke, M.; Preussel, K.; Lippert, I.; von Dohren, H. Diversity and distribution of Microcystis (Cyanobacteria) oligopeptide chemotypes from natural communities studied by single-colony mass spectrometry. Microbiology 2004, 150, 1785– 1796,  DOI: 10.1099/mic.0.26947-0
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      9
      Diversity and distribution of Microcystis (cyanobacteria) oligopeptide chemotypes from natural communities studied by single-colony mass spectrometry
      Welker, Martin; Brunke, Matthias; Preussel, Karina; Lippert, Indra; Von Doehren, Hans
      Microbiology (Reading, United Kingdom) (2004), 150 (6), 1785-1796CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
      Microcystis sp. has been recognized in recent years as a producer of a high no. of secondary metabolites. Among these, peptides that are produced by the nonribosomal peptide synthetase pathway often show bioactivity or are toxic to humans. The prodn. of particular peptides is specific for individual Microcystis clones, allowing their characterization as chemotypes by analyzing the peptidome. The authors studied the in situ diversity of peptides and chemotypes in Microcystis communities from lakes in and around Berlin, Germany, by direct anal. of individual colonies by MALDI-TOF mass spectrometry. From 165 colonies analyzed a total of 46 individual peptides could be identified, 21 of which have not been described previously. For six of the new peptides the structures could be elucidated from fragment patterns, while for others only a preliminary classification could be achieved. In most colonies, two to ten individual peptides were detected. In 19 colonies, 16 of which were identified as M. wesenbergii, no peptide metabolites could be detected. The peptide data of 146 colonies were subjected to an ordination (principal component anal.). The principal components were clearly formed by the microcystin variants Mcyst-LR, -RR and -YR, anabaenopeptins B and E/F, a putative microviridin, and a new cyanopeptolin. In the resulting ordination plots most colonies were grouped into five distinct groups, while 40 colonies scattered widely outside these groups. In some cases colonies from different lakes clustered closely, indicating the presence of similar chemotypes in the resp. samples. With respect to colony morphol. no clear correlation between a chemotype and a morphospecies could be established, but M. aeruginosa, for example, was found to produce predominantly microcystins. In contrast, M. ichthyoblabe colonies were mostly neg. for microcystins and instead produced anabaenopeptins. The no. of peptides detected in a limited no. of samples and the various combinations of peptides in individual Microcystis colonies highlights the immense metabolic potential and diversity of this genus.
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    10. 10
      Beversdorf, L. J.; Weirich, C. A.; Bartlett, S. L.; Miller, T. R. Variable cyanobacterial toxin and metabolite profiles across six eutrophic lakes of differing physiochemical characteristics. Toxins 2017, 9, 62,  DOI: 10.3390/toxins9020062
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      10
      Variable cyanobacterial toxin and metabolite profiles across six eutrophic lakes of differing physiochemical characteristics
      Beversdorf, Lucas J.; Weirich, Chelsea A.; Bartlett, Sarah L.; Miller, Todd. R.
      Toxins (2017), 9 (2), 62/1-62/21CODEN: TOXIB7; ISSN:2072-6651. (MDPI AG)
      Future sustainability of freshwater resources is seriously threatened due to the presence of harmful cyanobacterial blooms, and yet, the no., extent, and distribution of most cyanobacterial toxins-including "emerging" toxins and other bioactive compds.-are poorly understood. We measured 15 cyanobacterial compds.-including four microcystins (MC), saxitoxin (SXT), cylindrospermopsin (CYL), anatoxin-a (ATX) and homo-anatoxin-a (hATX), two anabaenopeptins (Apt), three cyanopeptolins (Cpt), microginin (Mgn), and nodularin (NOD)-in six freshwater lakes that regularly experience noxious cHABs. MC, a human liver toxin, was present in all six lakes and was detected in 80% of all samples. Similarly, Apt, Cpt, and Mgn were detected in all lakes in roughly 86%, 50%, and 35% of all samples, resp. Despite being a notable brackish water toxin, NOD was detected in the two shallowest lakes-Wingra (4.3 m) and Koshkonong (2.1 m). All compds. were highly variable temporally, and spatially. Metabolite profiles were significantly different between lakes suggesting lake characteristics influenced the cyanobacterial community and/or metabolite prodn. Understanding how cyanobacterial toxins are distributed across eutrophic lakes may shed light onto the ecol. function of these metabolites, provide valuable information for their remediation and removal, and aid in the protection of public health.
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    11. 11
      Bogialli, S.; Bortolini, C.; Di Gangi, I. M.; Di Gregorio, F. N.; Lucentini, L.; Favaro, G.; Pastore, P. Liquid chromatography-high resolution mass spectrometric methods for the surveillance monitoring of cyanotoxins in freshwaters. Talanta 2017, 170, 322– 330,  DOI: 10.1016/j.talanta.2017.04.033
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      11
      Liquid chromatography-high resolution mass spectrometric methods for the surveillance monitoring of cyanotoxins in freshwaters
      Bogialli, Sara; Bortolini, Claudio; Di Gangi, Iole Maria; Di Gregorio, Federica Nigro; Lucentini, Luca; Favaro, Gabriella; Pastore, Paolo
      Talanta (2017), 170 (), 322-330CODEN: TLNTA2; ISSN:0039-9140. (Elsevier B.V.)
      A comprehensive risk management on human exposure to cyanotoxins, whose prodn. is actually unpredictable, is limited by reliable anal. tools for monitoring as many toxic algal metabolites as possible. Two anal. approaches based on a LC-QTOF system for target anal. and suspect screening of cyanotoxins in freshwater were presented. A database with 369 compds. belonging to cyanobacterial metabolites was developed and used for a retrospective data anal. based on high resoln. mass spectrometry (HRMS). HRMS fragmentation of the suspect cyanotoxin precursor ions was subsequently performed for correctly identifying the specific variants. Alternatively, an automatic tandem HRMS anal. tailored for cyanotoxins was performed in a single chromatog. run, using the developed database as a preferred precursor ions list. Twenty-five exts. of surface and drinking waters contaminated by cyanobacteria were processed. The identification of seven uncommon microcystins (M(O)R, MC-FR, MSer7-YR, D-Asp3MSer7-LR, MSer7-LR, dmAdda-LR and dmAdda-YR) and 6 anabaenopeptins (A, B, F, MM850, MM864, oscyllamide Y) was reported. Several isobaric variants, fully sepd. by chromatog., were pointed out. The developed methods are proposed to be used by environmental and health agencies for strengthening the surveillance monitoring of cyanotoxins in water.
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    12. 12
      Kurmayer, R.; Deng, L.; Entfellner, E. Role of toxic and bioactive secondary metabolites in colonization and bloom formation by filamentous cyanobacteria Planktothrix. Harmful Algae 2016, 54, 69– 86,  DOI: 10.1016/j.hal.2016.01.004
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      12
      Role of toxic and bioactive secondary metabolites in colonization and bloom formation by filamentous cyanobacteria Planktothrix
      Kurmayer, Rainer; Deng, Li; Entfellner, Elisabeth
      Harmful Algae (2016), 54 (), 69-86CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
      A review. Bloom-forming cyanobacteria Planktothrix agardhii and P. rubescens are regularly involved in the occurrence of cyanotoxin in lakes and reservoirs. Besides microcystins (MCs), which inhibit eukaryotic protein phosphatase 1 and 2A, several families of bioactive peptides are produced, thereby resulting in impressive secondary metabolite structural diversity. This review will focus on the current knowledge of the phylogeny, morphol., and ecophysiol. adaptations of Planktothrix as well as the toxins and bioactive peptides produced. The relatively well studied ecophysiol. adaptations (buoyancy, shade tolerance, nutrient storage capacity) can partly explain the invasiveness of this group of cyanobacteria that bloom within short periods (weeks to months). The more recent elucidation of the genetic basis of toxin and bioactive peptide synthesis paved the way for investigating its regulation both in the lab. using cell cultures as well as under field conditions. The high frequency of several toxin and bioactive peptide synthesis genes obsd. within P. agardhii and P. rubescens, but not for other Planktothrix species (e.g. P. pseudagardhii), suggests a potential functional linkage between bioactive peptide prodn. and the colonization potential and possible dominance in habitats. It is hypothesized that, through toxin and bioactive peptide prodn., Planktothrix act as a niche constructor at the ecosystem scale, possibly resulting in an even higher ability to monopolize resources, pos. feedback loops, and resilience under stable environmental conditions. Thus, refocusing harmful algal bloom management by integrating ecol. and phylogenetic factors acting on toxin and bioactive peptide synthesis gene distribution and concns. could increase the predictability of the risks originating from Planktothrix blooms.
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    13. 13
      Otten, T. G.; Paerl, H. W.; Dreher, T. W.; Kimmerer, W. J.; Parker, A. E. The molecular ecology of Microcystis sp blooms in the San Francisco Estuary. Environ. Microbiol. 2017, 19, 3619– 3637,  DOI: 10.1111/1462-2920.13860
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      13
      The molecular ecology of Microcystis sp. blooms in the San Francisco Estuary
      Otten, Timothy G.; Paerl, Hans W.; Dreher, Theo W.; Kimmerer, Wim J.; Parker, Alexander E.
      Environmental Microbiology (2017), 19 (9), 3619-3637CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
      Summary : Harmful blooms of the cyanobacterium Microcystis sp. have become increasingly pervasive in the San Francisco Estuary Delta (USA) since the early 2000s and their rise has coincided with substantial decreases in several important fish species. Direct and indirect effects Microcystis blooms may have on the Delta food web were investigated. The Microcystis population was tracked for 2 years at six sites throughout the Delta using quant. PCR. High-throughput amplicon sequencing and colony PCR sequencing revealed the presence of 10 different strains of Microcystis, including 6 different microcystin-producing strains. Shotgun metagenomic anal. identified a variety of Microcystis secondary metabolite pathways, including those for the biosynthesis of: aeruginosin, cyanopeptolin, microginin, microviridin and piricyclamide. A sizable redn. was obsd. in microbial community diversity during a large Microcystis bloom (H' = 0.61) relative to periods preceding (H' = 2.32) or following (H' = 3.71) the bloom. Physicochem. conditions of the water column were stable throughout the bloom period. The elevated abundance of a cyanomyophage with high similarity to previously sequenced isolates known to infect Microcystis sp. was implicated in the bloom's collapse. Network anal. was employed to elucidate synergistic and antagonistic relationships between Microcystis and other bacteria and indicated that only very few taxa were pos. correlated with Microcystis.
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    14. 14
      Le Manach, S.; Duval, C.; Marie, A.; Djediat, C.; Catherine, A.; Edery, M.; Bernard, C.; Marie, B. Global metabolomic characterizations of Microcystis spp. highlights clonal diversity in natural bloom-forming populations and expands metabolite structural diversity. Front. Microbiol. 2019, 10, 791  DOI: 10.3389/fmicb.2019.00791
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      14
      Global Metabolomic Characterizations of Microcystis spp. Highlights Clonal Diversity in Natural Bloom-Forming Populations and Expands Metabolite Structural Diversity
      Le Manach Severine; Duval Charlotte; Marie Arul; Djediat Chakib; Catherine Arnaud; Edery Marc; Bernard Cecile; Marie Benjamin
      Frontiers in microbiology (2019), 10 (), 791 ISSN:1664-302X.
      Cyanobacteria are photosynthetic prokaryotes capable of synthesizing a large variety of secondary metabolites that exhibit significant bioactivity or toxicity. Microcystis constitutes one of the most common cyanobacterial genera, forming the intensive blooms that nowadays arise in freshwater ecosystems worldwide. Species in this genus can produce numerous cyanotoxins (i.e., toxic cyanobacterial metabolites), which can be harmful to human health and aquatic organisms. To better understand variations in cyanotoxin production between clones of Microcystis species, we investigated the diversity of 24 strains isolated from the same blooms or from different populations in various geographical areas. Strains were compared by genotyping with 16S-ITS fragment sequencing and metabolite chemotyping using LC ESI-qTOF mass spectrometry. While genotyping can help to discriminate among different species, the global metabolome analysis revealed clearly discriminating molecular profiles among strains. These profiles could be clustered primarily according to their global metabolite content, then according to their genotype, and finally according to their sampling location. A global molecular network of all metabolites produced by Microcystis species highlights the production of a wide set of chemically diverse metabolites, including a few microcystins, many aeruginosins, microginins, cyanopeptolins, and anabaenopeptins, together with a large set of unknown molecules. These components, which constitute the molecular biodiversity of Microcystis species, still need to be investigated in terms of their structure and potential bioactivites (e.g., toxicity).
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    15. 15
      Sanz, M.; Andreote, A. P. D.; Fiore, M. F.; Dorr, F. A.; Pinto, E. Structural characterization of new peptide variants produced by cyanobacteria from the Brazilian atlantic coastal forest using liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry. Mar. Drugs 2015, 13, 3892– 3919,  DOI: 10.3390/md13063892
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      15
      Structural characterization of new peptide variants produced by cyanobacteria from the Brazilian atlantic coastal forest using liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry
      Sanz, Miriam; Andreote, Ana Paula Dini; Fiore, Marli Fatima; Dorr, Felipe Augusto; Pinto, Ernani
      Marine Drugs (2015), 13 (6), 3892-3919CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      Cyanobacteria from underexplored and extreme habitats are attracting increasing attention in the search for new bioactive substances. However, cyanobacterial communities from tropical and subtropical regions are still largely unknown, esp. with respect to metabolite prodn. Among the structurally diverse secondary metabolites produced by these organisms, peptides are by far the most frequently described structures. In this work, liq. chromatog./electrospray ionization coupled to high resoln. quadrupole time of- flight tandem mass spectrometry with pos. ion detection was applied to study the peptide profile of a group of cyanobacteria isolated from the Southeastern Brazilian coastal forest. A total of 38 peptides belonging to three different families (anabaenopeptins, aeruginosins, and cyanopeptolins) were detected in the exts. Of the 38 peptides, 37 were detected here for the first time. New structural features were proposed based on mass accuracy data and isotopic patterns derived from full scan and MS/MS spectra. Interestingly, of the 40 surveyed strains only nine were confirmed to be peptide producers; all of these strains belonged to the order Nostocales (three Nostoc sp., two Desmonostoc sp. and four Brasilonema sp.).
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    16. 16
      Mazur-Marzec, H.; Bertos-Fortis, M.; Torunska-Sitarz, A.; Fidor, A.; Legrand, C. Chemical and genetic diversity of Nodularia spumigena from the Baltic Sea. Mar. Drugs 2016, 14, 209  DOI: 10.3390/md14110209
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      16
      Chemical and genetic diversity of Nodularia spumigena from the Baltic Sea
      Mazur-Marzec, Hanna; Bertos-Fortis, Mireia; Torunska-Sitarz, Anna; Fidor, Anna; Legrand, Catherine
      Marine Drugs (2016), 14 (11), 209/1-209/14CODEN: MDARE6; ISSN:1660-3397. (MDPI AG)
      Nodularia spumigena is a toxic, filamentous cyanobacterium occurring in brackish waters worldwide, yet forms extensive recurrent blooms in the Baltic Sea. N. spumigena produces several classes of non-ribosomal peptides (NRPs) that are active against several key metabolic enzymes. Previously, strains from geog. distant regions showed distinct NRP metabolic profiles. In this work, conspecific diversity in N. spumigena was studied using chem. and genetic approaches. NRP profiles were detd. in 25 N. spumigena strains isolated in different years and from different locations in the Baltic Sea using liq. chromatog.-tandem mass spectrometry (LC-MS/MS). Genetic diversity was assessed by targeting the phycocyanin intergenic spacer and flanking regions (cpcBA-IGS). Overall, 14 spumigins, 5 aeruginosins, 2 pseudaeruginosins, 2 nodularins, 36 anabaenopeptins, and one new cyanopeptolin-like peptide were identified among the strains. Seven anabaenopeptins were new structures; one cyanopeptolin-like peptide was discovered in N. spumigena for the first time. Based on NRP profiles and cpcBA-IGS sequences, the strains were grouped into two main clusters without apparent influence of year and location, indicating persistent presence of these two subpopulations in the Baltic Sea. This study is a major step in using chem. profiling to explore conspecific diversity with a higher resoln. than with a sole genetic approach.
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    17. 17
      Carneiro, R. L.; Dorr, F. A.; Dorr, F.; Bortoli, S.; Delherbe, N.; Vasquez, M.; Pinto, E. Co-occurrence of microcystin and microginin congeners in Brazilian strains of Microcystis sp. FEMS Microbiol. Ecol. 2012, 82, 692– 702,  DOI: 10.1111/j.1574-6941.2012.01439.x
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      Co-occurrence of microcystin and microginin congeners in Brazilian strains of Microcystis sp.
      Carneiro, Ronaldo Leal; Dorr, Felipe Augusto; Dorr, Fabiane; Bortoli, Stella; Delherbe, Nathalie; Vasquez, Monica; Pinto, Ernani
      FEMS Microbiology Ecology (2012), 82 (3), 692-702CODEN: FMECEZ; ISSN:0168-6496. (Wiley-Blackwell)
      Species of Microcystis are the most common bloom-forming cyanobacteria in several countries. Despite extensive studies regarding the prodn. of bioactive cyanopeptides in this genus, there are limited data on isolated strains from Brazil. Three Microcystis sp. strains were isolated from the Salto Grande Reservoir (LTPNA01, 08 and 09) and studied for the presence of mcy genes, microcystins and other cyanopeptides. Microcystin and microginin prodn. was confirmed in two isolates using high-resoln. tandem mass spectrometry after electrospray ionization (ESI-Q-TOF), and the structures of two new microginin congeners are proposed (MG756 Ahda-Val-Leu-Hty-Tyr and MG770 MeAhda-Val-Leu-Hty-Tyr). The biosynthesis profile of the identified cyanopeptides was evaluated at different growth phases via a newly developed HPLC-UV method. Results demonstrated no substantial differences in the prodn. of microcystins and microginins after data normalization to cell quota, suggesting a constitutive biosynthesis. This study represents the first confirmed co-prodn. of microginins and microcystins in Brazilian strains of Microcystis sp. and highlights the potential of Brazilian cyanobacteria as a source of natural compds. with pharmaceutical interest.
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    18. 18
      Chorus, I.; Sivonen, K.; Codd, G. A.; Börner, T.; Von Doehren, H.; Welker, M.; Dittmann, E.; Claussner, Y.; Christopffersen, K.; Scober, E.; Utliken, H.; Rohrlack, T.; Lyck, S.; Visser, P. M.; Tonk, L.; Dietrich, D. R.; Hoeger, S. J.; Tandeau de Marsac, N.; Iteman, I.; Niesel, V.; Fastner, J.; Grummt, T.; Heinze, R.; Ferreira, A.-H.; Warming-Svendsen, T.; Flieger, I.; Wessel, G.; Rouhiainen, L.; Morrison, L. F. Toxic and Bioactive Peptides in Cyanobacteria—PEPCY Report , 2006.
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      Janssen, E. M. L. Cyanobacterial peptides beyond microcystins - a review on co-occurrence, toxicity, and challenges for risk assessment. Water Res. 2019, 151, 488– 499,  DOI: 10.1016/j.watres.2018.12.048
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      19
      Cyanobacterial peptides beyond microcystins - A review on co-occurrence, toxicity, and challenges for risk assessment
      Janssen, Elisabeth M.-L.
      Water Research (2019), 151 (), 488-499CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
      Cyanobacterial bloom events that produce natural toxins occur in freshwaters across the globe, yet the potential risk of many cyanobacterial metabolites remains mostly unknown. Only microcystins, one class of cyanopeptides, have been studied intensively and the wealth of evidence regarding exposure concns. and toxicity led to their inclusion in risk management frameworks for water quality. However, cyanobacteria produce an incredible diversity of hundreds of cyanopeptides beyond the class of microcystins. The question arises, whether the other cyanopeptides are in fact of no human and ecol. concern or whether these compds. merely received (too) little attention thus far. Current observations suggest that an assessment of their (eco)toxicol. risk is indeed relevant: First, other cyanopeptides, including cyanopeptolins and anabaenopeptins, can occur just as frequently and at similar nanomolar concns. as microcystins in surface waters. Second, cyanopeptolins, anabaenopeptins, aeruginosins and microginins inhibit proteases in the nanomolar range, in contrast to protein phosphatase inhibition by microcystins. Cyanopeptolins, aeruginosins, and aerucyclamide also show toxicity against grazers in the micromolar range comparable to microcystins. The key challenge for a comprehensive risk assessment of cyanopeptides remains their large structural diversity, lack of ref. stds., and high anal. requirements for identification and quantification. One way forward would be a prevalence study to identify the priority candidates of tentatively abundant, persistent, and toxic cyanopeptides to make comprehensive risk assessments more manageable.
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    20. 20
      Beversdorf, L. J.; Rude, K.; Weirich, C. A.; Bartlett, S. L.; Seaman, M.; Kozik, C.; Biese, P.; Gosz, T.; Suha, M.; Stempa, C.; Shaw, C.; Hedman, C.; Piatt, J. J.; Miller, T. R. Analysis of cyanobacterial metabolites in surface and raw drinking waters reveals more than microcystin. Water Res. 2018, 140, 280– 290,  DOI: 10.1016/j.watres.2018.04.032
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      20
      Analysis of cyanobacterial metabolites in surface and raw drinking waters reveals more than microcystin
      Beversdorf, Lucas J.; Rude, Kayla; Weirich, Chelsea A.; Bartlett, Sarah L.; Seaman, Mary; Kozik, Christine; Biese, Peter; Gosz, Timothy; Suha, Michael; Stempa, Christopher; Shaw, Christopher; Hedman, Curtis; Piatt, Joseph J.; Miller, Todd R.
      Water Research (2018), 140 (), 280-290CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
      Freshwater cyanobacterial blooms are becoming increasingly problematic in regions that rely on surface waters for drinking water prodn. Microcystins (MCs) are toxic peptides produced by multiple cyanobacterial genera with a global occurrence. Cyanobacteria also produce a variety of other toxic and/or otherwise bioactive peptides (TBPs) that have gained less attention including cyanopeptolins (Cpts), anabaenopeptins (Apts), and microginins (Mgn). In this study, we compared temporal and spatial trends of four MCs (MCLR, MCRR, MCYR, MCLA), three Cpts (Cpt1020, Cpt1041, Cpt1007), two Apts (AptF, AptB), and Mgn690 in raw drinking water and at six surface water locations above these drinking water intakes in a eutrophic lake. All four MC congeners and five of six TBPs were detected in lake and raw drinking water. Across all samples, MCLR was the most frequently detected metabolite (100% of samples) followed by MCRR (97%) > Cpt1007 (74%) > MCYR (69%) > AptF (67%) > MCLA (61%) > AptB (54%) > Mgn690 (29%) and Cpt1041 (15%). Mean concns. of MCs, Apts, and Cpts into two drinking water intakes were 3.9± 4.7, 0.14± 0.21, and 0.38± 0.92, resp. Mean concns. in surface water were significantly higher (p<0.05) than in drinking water intakes for MCs but not for Cpts and Apts. Temporal trends in MCs, Cpts, and Apts in the two raw drinking water intakes were significantly correlated (p < 0.05) with measures of cell abundance (chlorophyll-a, Microcystis cell d.), UV absorbance, and turbidity in surface water. This study expands current information about cyanobacterial TBPs that occur in lakes and that enter drinking water treatment plants and underscores the need to det. the fate of less studied cyanobacterial metabolites during drinking water treatment that may exacerbate toxicity of more well-known cyanobacterial toxins.
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    21. 21
      Lee, S. J.; Jang, M. H.; Kim, H. S.; Yoon, B. D.; Oh, H. M. Variation of microcystin content of Microcystis aeruginosa relative to medium N: P ratio and growth stage. J. Appl. Microbiol. 2000, 89, 323– 329,  DOI: 10.1046/j.1365-2672.2000.01112.x
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      21
      Variation of microcystin content of Microcystis aeruginosa relative to medium N:P ratio and growth stage
      Lee, S. J.; Jang, M. -H.; Kim, H. -S.; Yoon, B. -D.; Oh, H. -M.
      Journal of Applied Microbiology (2000), 89 (2), 323-329CODEN: JAMIFK; ISSN:1364-5072. (Blackwell Science Ltd.)
      Changes in the microcystin content of Microcystis aeruginosa UTEX 2388 were investigated at several N:P ratios of the medium and various growth stages. Under the P-fixed condition, the microcystin content of the cells changed with different medium N:P ratios, with the highest at 2748 μg g-1 at a N:P ratio of 16 after incubation for 7 d. The microcystin content of M. aeruginosa exhibited a high correlation with the total N content regardless of an N-fixed or P-fixed culture. When the N:P ratio of the medium was fixed to 16:1, the microcystin content of M. aeruginosa at various growth stages was highest at 2191 μg g-1 after an incubation of 4 d and the chlorophyll a content showed a similar tendency. There was a highly significant relationship between the microcystin content of M. aeruginosa and the chlorophyll a concn. in the culture during the incubation. Accordingly, the microcystin content of M. aeruginosa during incubation can be easily estd. and monitored by measuring the in vivo fluorescence changes in the culture.
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    22. 22
      Repka, S.; Koivula, M.; Harjunpa, V.; Rouhiainen, L.; Sivonen, K. Effects of phosphate and light on growth of and bioactive peptide production by the cyanobacterium Anabaena strain 90 and its anabaenopeptilide mutant. Appl. Environ. Microbiol. 2004, 70, 4551– 4560,  DOI: 10.1128/AEM.70.8.4551-4560.2004
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      22
      Effects of phosphate and light on growth of and bioactive peptide production by the cyanobacterium Anabaena strain 90 and its anabaenopeptilide mutant
      Repka, Sari; Koivula, Minna; Harjunpae, Vesa; Rouhiainen, Leo; Sivonen, Kaarina
      Applied and Environmental Microbiology (2004), 70 (8), 4551-4560CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
      Cyanobacteria synthesize several types of bioactive secondary metabolites. Anabaena strain 90 produces three types of bioactive peptides, microcystins (inhibitors of protein phosphatases 1 and 2A), anabaenopeptilides, and anabaenopeptins (serine protease inhibitors). To investigate the role of the anabaenopeptilides in Anabaena, wild-type strain 90 (WT) and its anabaenopeptilide deficient mutant (MU) were cultured with various light and phosphate levels to evaluate the effects and coeffects of these growth factors on the concns. of the three classes of peptides and the growth characteristics. WT and MU grew in comparable ways under the different growth conditions. The total peptide concn. in WT was significantly higher than that in MU (2.5 and 1.4 μg/mg [dry wt.], resp.). Interestingly, the av. concn. of anabaenopeptins was significantly higher in MU than in WT (0.59 and 0.24 μg/mg [dry wt.], resp.). The concn. of microcystins was slightly but not statistically significantly higher in MU than in WT (1.0 and 0.86 μg/mg [dry wt.], resp.). In WT, the highest peptide concns. were usually found after 13 days in cultures grown at medium light intensities (23 μmol m-2 s-1) and with the highest phosphate concns. (2,600 μg liter-1). In MU, the highest peptide concns. were found in 13-day-old cultures grown at medium light intensities (23 μmol m-2 s-1) and with phosphate concns. greater than 100 μg liter-1. The higher concns. of anabaenopeptins in MU may compensate for the absence of anabaenopeptilides. These findings clearly indicate that these compds. may have some linked function in the producer organism, the nature of which remains to be discovered.
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    23. 23
      Tonk, L.; Welker, M.; Huisman, J.; Visser, P. M. Production of cyanopeptolins, anabaenopeptins, and microcystins by the harmful cyanobacteria Anabaena 90 and Microcystis PCC 7806. Harmful Algae 2009, 8, 219– 224,  DOI: 10.1016/j.hal.2008.05.005
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      23
      Production of cyanopeptolins, anabaenopeptins, and microcystins by the harmful cyanobacteria Anabaena 90 and Microcystic PCC 7806
      Tonk, Linda; Welker, Martin; Huisman, Jef; Visser, Petra M.
      Harmful Algae (2009), 8 (2), 219-224CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
      This study investigated the effects of light intensity, temp., and phosphorus limitation on the peptide prodn. of the cyanobacteria Microcystis PCC 7806 and Anabaena 90. Microcystis PCC 7806 produced two microcystin variants and three cyanopeptolins, whereas Anabaena 90 produced four microcystin variants, three anabaenopeptins, and two anabaenopeptilides. Microcystin and cyanopeptolin contents varied by a factor 2-3, whereas the anabaenopeptins and anabaenopeptilides of Anabaena varied more strongly. Under phosphorus limitation, peptide prodn. rates increased with the specific growth rate. The response of peptide prodn. to light intensity and temp. was more complex: in many cases peptide prodn. decreased with specific growth rate. We obsd. compensatory changes of different peptide variants: decreased cyanopeptolin A and C contents were accompanied by increased cyanopeptolin 970 contents, and decreased anabaenopeptin A and C contents were accompanied by increased anabaenopeptilide 90B contents. Compensatory dynamics in peptide prodn. may enable cyanobacteria to sustain stable peptide levels in a variable environment.
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    24. 24
      Dai, R. H.; Wang, P. F.; Jia, P. L.; Zhang, Y.; Chu, X. C.; Wang, Y. F. A review on factors affecting microcystins production by algae in aquatic environments. World J. Microbiol. Biotechnol. 2016, 32, 51  DOI: 10.1007/s11274-015-2003-2
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      24
      A review on factors affecting microcystins production by algae in aquatic environments
      Dai Ruihua; Wang Pinfei; Jia Peili; Zhang Yi; Chu Xincheng; Wang Yifei
      World journal of microbiology & biotechnology (2016), 32 (3), 51 ISSN:.
      Microcystins, a toxin produced by Microcystis aeruginosa have become a global environmental issue in recent years. As a consequence of eutrophication, microcystins have become widely disseminated in drinking water sources, seriously impairing drinking water quality. This review focuses on the relationship between microcystins synthesis and physical, chemical, and biological environmental factors that are significant in controlling their production. Light intensity and temperature are the more important physical factors, and in many cases, an optimum level for these two factors has been observed. Nitrogen and phosphorus are the key chemical factors causing frequent occurrence of harmful algal blooms and microcystins production. The absorption of nutrients and metabolic activities of algae are affected by different concentrations and forms of nitrogen and phosphorus, leading to variations in microcystins production Metal ions and emerging pollutants are other significant chemical factors, whose comprehensive impact is still being studied. Algae can also interact with biological agents like predators and competitors in aquatic environments, and such interactions are suggested to promote MCs production and release. This review further highlights areas that require further research in order to gain a better understanding of microcystins production. It provides a theoretical basis for the control of microcystins production and releasing into aquatic environments.
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      Dolman, A. M.; Rucker, J.; Pick, F. R.; Fastner, J.; Rohrlack, T.; Mischke, U.; Wiedner, C. Cyanobacteria and cyanotoxins: the influence of nitrogen versus phosphorus. PLoS One 2012, 7, e38757  DOI: 10.1371/journal.pone.0038757
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      Cyanobacteria and cyanotoxins: the influence of nitrogen versus phosphorus
      Dolman, Andrew M.; Ruecker, Jacqueline; Pick, Frances R.; Fastner, Jutta; Rohrlack, Thomas; Mischke, Ute; Wiedner, Claudia
      PLoS One (2012), 7 (6), e38757CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      The importance of N vs. P in explaining total cyanobacterial biovolume, the biovolume of specific cyanobacterial taxa, and the incidence of cyanotoxins was detd. for 102 North German lakes, using methods to sep. the effects of joint variation in N and P concn. from those of differential variation in N vs. P. While the pos. relationship between total cyanobacteria biovolume and P concn. disappeared at high P concns., cyanobacteria biovolume increased continually with N concn., indicating potential N limitation in highly P enriched lakes. The biovolumes of all cyanobacterial taxa were higher in lakes with above av. joint NP concns., although the relative biovolumes of some Nostocales were higher in less enriched lakes. Taxa were found to have diverse responses to differential N vs. P concn., and the differences between taxa were not consistent with the hypothesis that potentially N2-fixing Nostocales taxa would be favored in low N relative to P conditions. In particular Aphanizomenon gracile and the subtropical invasive species Cylindrospermopsis raciborskii often reached their highest biovolumes in lakes with high nitrogen relative to phosphorus concn. Concns. of all cyanotoxin groups increased with increasing TP and TN, congruent with the biovolumes of their likely producers. Microcystin concn. was strongly correlated with the biovolume of Planktothrix agardhii but concns. of anatoxin, cylindrospermopsin and paralytic shellfish poison were not strongly related to any individual taxa. Cyanobacteria should not be treated as a single group when considering the potential effects of changes in nutrient loading on phytoplankton community structure and neither should the N2-fixing Nostocales. This is of particular importance when considering the occurrence of cyanotoxins, as the two most abundant potentially toxin producing Nostocales in our study were found in lakes with high N relative to P enrichment.
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      Tromas, N.; Taranu, Z. E.; Martin, B. D.; Willis, A.; Fortin, N.; Greer, C. W.; Shapiro, B. J. Niche separation increases with Genetic distance among bloom-forming cyanobacteria. Front. Microbiol. 2018, 9, 438  DOI: 10.3389/fmicb.2018.00438
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      Niche Separation Increases With Genetic Distance Among Bloom-Forming Cyanobacteria
      Tromas Nicolas; Shapiro B Jesse; Taranu Zofia E; Martin Bryan D; Willis Amy; Willis Amy; Fortin Nathalie; Greer Charles W
      Frontiers in microbiology (2018), 9 (), 438 ISSN:1664-302X.
      Bacterial communities are composed of distinct groups of potentially interacting lineages, each thought to occupy a distinct ecological niche. It remains unclear, however, how quickly niche preference evolves and whether more closely related lineages are more likely to share ecological niches. We addressed these questions by following the dynamics of two bloom-forming cyanobacterial genera over an 8-year time-course in Lake Champlain, Canada, using 16S amplicon sequencing and measurements of several environmental parameters. The two genera, Microcystis (M) and Dolichospermum (D), are frequently observed simultaneously during bloom events and thus have partially overlapping niches. However, the extent of their niche overlap is debated, and it is also unclear to what extent niche partitioning occurs among strains within each genus. To identify strains within each genus, we applied minimum entropy decomposition (MED) to 16S rRNA gene sequences. We confirmed that at a genus level, M and D have different preferences for nitrogen and phosphorus concentrations. Within each genus, we also identified strains differentially associated with temperature, precipitation, and concentrations of nutrients and toxins. In general, niche similarity between strains (as measured by co-occurrence over time) declined with genetic distance. This pattern is consistent with habitat filtering - in which closely related taxa are ecologically similar, and therefore tend to co-occur under similar environmental conditions. In contrast with this general pattern, similarity in certain niche dimensions (notably particulate nitrogen and phosphorus) did not decline linearly with genetic distance, and instead showed a complex polynomial relationship. This observation suggests the importance of processes other than habitat filtering - such as competition between closely related taxa, or convergent trait evolution in distantly related taxa - in shaping particular traits in microbial communities.
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    27. 27
      Xie, L. Q.; Xie, P.; Li, S. X.; Tang, H. J.; Liu, H. The low TN: TP ratio, a cause or a result of Microcystis blooms?. Water Res. 2003, 37, 2073– 2080,  DOI: 10.1016/S0043-1354(02)00532-8
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      27
      The low TN:TP ratio, a cause or a result of Microcystis blooms?
      Xie, Liqiang; Xie, Ping; Li, Sixin; Tang, Huijuan; Liu, Hong
      Water Research (2003), 37 (9), 2073-2080CODEN: WATRAG; ISSN:0043-1354. (Elsevier Science Ltd.)
      An enclosure expt. in the shallow, subtropical Lake Donghu, China, was performed in the summer of 2001 to examine the effect of TN:TP (total P) ratios and P-redn. on the occurrence of Microcystis blooms. The treatments were performed with enough amts. of N but with different amts. of P in the water column and sediment. Microcystis blooms occurred in the enclosures either with an initial TN:TP <29 or TN:TP>29 where the nutrients (N, P) were high enough. Microcystis blooms never occurred in the treatments with low P concn. in spite of the presence of sufficient N. The P-rich sediments served as an important source for the P supply in the water column, and such a process was activated greatly by the outburst of Microcystis blooms which pumped up selectively P from the sediments and thus decreased the TN:TP ratios. Therefore, the low TN:TP ratio is not a cause but rather a result of Microcystis blooms.
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    28. 28
      Chia, M. A.; Jankowiak, J. G.; Kramer, B. J.; Goleski, J. A.; Huang, I.-S.; Zimba, P. V.; do Carmo Bittencourt-Oliveira, M.; Gobler, C. J. Succession and toxicity of Microcystis and Anabaena (Dolichospermum) blooms are controlled by nutrient-dependent allelopathic interactions. Harmful Algae 2018, 74, 67– 77,  DOI: 10.1016/j.hal.2018.03.002
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      Succession and toxicity of Microcystis and Anabaena (Dolichospermum) blooms are controlled by nutrient-dependent allelopathic interactions
      Chia, Mathias A.; Jankowiak, Jennifer G.; Kramer, Benjamin J.; Goleski, Jennifer A.; Huang, I.-Shuo; Zimba, Paul V.; Bittencourt-Oliveira, Maria do Carmo; Gobler, Christopher J.
      Harmful Algae (2018), 74 (), 67-77CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
      Microcystis and Anabaena (Dolichospermum) are among the most toxic cyanobacterial genera and often succeed each other during harmful algal blooms. The role allelopathy plays in the succession of these genera is not fully understood. The allelopathic interactions of six strains of Microcystis and Anabaena under different nutrient conditions in co-culture and in culture-filtrate expts. were investigated. Microcystis strains significantly reduced the growth of Anabaena strains in mixed cultures with direct cell-to-cell contact and high nutrient levels. Cell-free filtrate from Microcystis cultures proved equally potent in suppressing the growth of nutrient replete Anabaena cultures while also significantly reducing anatoxin-a prodn. Allelopathic interactions between Microcystis and Anabaena were, however, partly dependent on ambient nutrient levels. Anabaena dominated under low N conditions and Microcystis dominated under nutrient replete and low P during which allelochems. caused the complete suppression of nitrogen fixation by Anabaena and stimulated glutathione S-transferase activity. The microcystin content of Microcystis was lowered with decreasing N and the presence of Anabaena decreased it further under low P and high nutrient conditions. Collectively, these results indicate that strong allelopathic interactions between Microcystis and Anabaena are closely intertwined with the availability of nutrients and that allelopathy may contribute to the succession, nitrogen availability, and toxicity of cyanobacterial blooms.
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    29. 29
      Oh, H. M.; Lee, S. J.; Jang, M. H.; Yoon, B. D. Microcystin production by Microcystis aeruginosa in a phosphorus-limited chemostat. Appl. Environ. Microbiol. 2000, 66, 176– 179,  DOI: 10.1128/AEM.66.1.176-179.2000
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      Microcystin production by Microcystis aeruginosa in a phosphorus-limited chemostat
      Oh, Hee-Mock; Lee, Seog June; Jang, Min-Ho; Yoon, Byung-Dae
      Applied and Environmental Microbiology (2000), 66 (1), 176-179CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
      The prodn. of microcystins (MC) from Microcystis aeruginosa UTEX 2388 was investigated in a P-limited continuous culture. MC (MC-LR, MC-RR, and MC-YR) from lyophilized M. aeruginosa were extd. with 5% acetic acid, purified by a Sep-Pak C18 cartridge, and then analyzed by high-performance liq. chromatog. with a UV detector and Nucleosil C18 reverse-phase column. The specific growth rate (μ) of M. aeruginosa was within the range of 0.1 to 0.8/day and was a function of the cellular P content under a P limitation. The N/P at. ratio of steady-state cells in a P-limited medium varied from 24 to 15 with an increasing μ. The MC-LR and MC-RR contents on a dry wt. basis were highest at μ of 0.1/day at 339 and 774 μg g-1, resp., while MC-YR was not detected. The MC content of M. aeruginosa was higher at a lower μ, whereas the MC-producing rate was linearly proportional to μ. The C fixation rate at an ambient irradiance (160 microeinsteins m-2 s-1) increased with μ. The ratios of the MC-producing rate to the C fixation rate were higher at a lower μ. Accordingly, the growth of M. aeruginosa was reduced under a P limitation due to a low C fixation rate, whereas the MC content was higher. Consequently, increases in the MC content per dry wt. along with the prodn. of the more toxic form, MC-LR, were obsd. under more P-limited conditions.
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    30. 30
      Pimentel, J. S. M.; Giani, A. Microcystin production and regulation under nutrient stress conditions in toxic Microcystis strains. Appl. Environ. Microbiol. 2014, 80, 5836– 5843,  DOI: 10.1128/AEM.01009-14
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      30
      Microcystin production and regulation under nutrient stress conditions in toxic Microcystis strains
      Pimentel, Juliana S. M.; Giani, Alessandra
      Applied and Environmental Microbiology (2014), 80 (18), 5836-5843, 9 pp.CODEN: AEMIDF; ISSN:1098-5336. (American Society for Microbiology)
      Microcystin is a common and well-known cyanobacterial toxin whose intracellular role is still under investigation. Increasing knowledge on microcystin gene expression and regulation can contribute to the understanding of its putative cellular function. In this work, reverse transcription-quant. PCR (RT-qPCR) was used to investigate the transcriptional response of the mcyD gene to nitrogen (nitrate and ammonium) and phosphorus limitation in two toxic Microcystis strains. The existence of a direct correlation between transcripts of mcyD and ntcA genes was also identified. In previous studies, NtcA (global nitrogen regulator) has been described as a potential component in the control of microcystin biosynthesis. This research showed that stress agents linked to nutrient deprivation could lead to a significant increase of microcystin prodn. in both strains studied. The more toxic strain proved to be more resistant to nutrient limitation. The similar outcomes of mcyD regulation obsd. for all nutrients suggest that this response can be linked to oxidative stress of cells undergoing adverse growth conditions.
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    31. 31
      Davis, T. W.; Berry, D. L.; Boyer, G. L.; Gobler, C. J. The effects of temperature and nutrients on the growth and dynamics of toxic and non-toxic strains of microcystis during cyanobacteria blooms. Harmful Algae 2009, 8, 715– 725,  DOI: 10.1016/j.hal.2009.02.004
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      The effects of temperature and nutrients on the growth and dynamics of toxic and non-toxic strains of microcystis during cyanobacteria blooms
      Davis, Timothy W.; Berry, Dianna L.; Boyer, Gregory L.; Gobler, Christopher J.
      Harmful Algae (2009), 8 (5), 715-725CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
      In temperate latitudes, toxic cyanobacteria blooms often occur in eutrophied ecosystems during warm months. Many common bloom-forming cyanobacteria have toxic and non-toxic strains which co-occur and are visually indistinguishable but can be quantified molecularly. Toxic Microcystis cells possess a suite of microcystin synthesis genes (mcyA-mcyJ), while non-toxic strains do not. For this study, we assessed the temporal dynamics of toxic and non-toxic strains of Microcystis by quantifying the microcystin synthetase gene (mcyD) and the small subunit rRNA gene, 16S (an indicator of total Microcystis), from samples collected from four lakes across the Northeast US over a two-year period. Nutrient concns. and water quality were measured and expts. were conducted which examd. the effects of elevated levels of temps. (+4 °C), nitrogen, and phosphorus on the growth rates of toxic and non-toxic strains of Microcystis. During the study, toxic Microcystis cells comprised between 12% and 100% of the total Microcystis population in Lake Ronkonkoma, NY, and between 0.01% and 6% in three other systems. In all lakes, mol. quantification of toxic (mcyD-possessing) Microcystis was a better predictor of in situ microcystin levels than total cyanobacteria, total Microcystis, chlorophyll a, or other factors, being significantly correlated with the toxin in every lake studied. Exptl. enhanced temps. yielded significantly increased growth rates of toxic Microcystis in 83% of expts. conducted, but did so for non-toxic Microcystis in only 33% of expts., suggesting that elevated temps. yield more toxic Microcystis cells and/or cells with more mcyD copies per cell, with either scenario potentially yielding more toxic blooms. Furthermore, concurrent increases in temp. and P concns. yielded the highest growth rates of toxic Microcystis cells in most expts. suggesting that future eutrophication and climatic warming may additively promote the growth of toxic, rather than non-toxic, populations of Microcystis, leading to blooms with higher microcystin content.
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      Harke, M. J.; Gobler, C. J. Global Transcriptional responses of the toxic cyanobacterium, Microcystis aeruginosa, to nitrogen stress, phosphorus stress, and growth on organic matter. PLoS One 2013, 8, e69834  DOI: 10.1371/journal.pone.0069834
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      32
      Global transcriptional responses of the toxic cyanobacterium, Microcystis aeruginosa, to nitrogen stress, phosphorus stress, and growth on organic matter
      Harke, Matthew J.; Gobler, Christopher J.
      PLoS One (2013), 8 (7), e69834CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Whole transcriptome shotgun sequencing (RNA-seq) was used to assess the transcriptomic response of the toxic cyanobacterium Microcystis aeruginosa during growth with low levels of dissolved inorg. nitrogen (low N), low levels of dissolved inorg. phosphorus (low P), and in the presence of high levels of high mol. wt. dissolved org. matter (HMWDOM). Under low N, one third of the genome was differentially expressed, with significant increases in transcripts obsd. among genes within the nir operon, urea transport genes (urtBCDE), and amino acid transporters while significant decreases in transcripts were obsd. in genes related to photosynthesis. There was also a significant decrease in the transcription of the microcystin synthetase gene set under low N and a significant decrease in microcystin content per Microcystis cell demonstrating that N supply influences cellular toxicity. Under low P, 27% of the genome was differentially expressed. The Pho regulon was induced leading to large increases in transcript levels of the alk. phosphatase phoX, the Pst transport system (pstABC), and the sphX gene, and transcripts of multiple sulfate transporter were also significantly more abundant. While the transcriptional response to growth on HMWDOM was smaller (5-22 % of genes differentially expressed), transcripts of multiple genes specifically assocd. with the transport and degrdn. of org. compds. were significantly more abundant within HMWDOM treatments and thus may be recruited by Microcystis to utilize these substrates. Collectively, these findings provide a comprehensive understanding of the nutritional physiol. of this toxic, bloom-forming cyanobacterium and the role of N in controlling microcystin synthesis.
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      Yu, L.; Kong, F. X.; Zhang, M.; Yang, Z.; Shi, X. L.; Du, M. Y. The dynamics of Microcystis genotypes and microcystin production and associations with environmental factors during blooms in Lake Chaohu, China. Toxins 2014, 6, 3238– 3257,  DOI: 10.3390/toxins6123238
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      The dynamics of Microcystis genotypes and microcystin production and associations with environmental factors during blooms in Lake Chaohu, China
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      Toxins (2014), 6 (12), 3238-3257CODEN: TOXIB7; ISSN:2072-6651. (MDPI AG)
      Lake Chaohu, which is a large, shallow, hypertrophic freshwater lake in southeastern China, has been experiencing lake-wide toxic Microcystis blooms in recent decades. To illuminate the relationships between microcystin (MC) prodn., the genotypic compn. of the Microcystis community and environmental factors, water samples and assocd. environmental data were collected from June to Oct. 2012 within Lake Chaohu. The Microcystis genotypes and MC concns. were quantified using quant. real-time PCR (qPCR) and HPLC, resp. The results showed that the abundances of Microcystis genotypes and MC concns. varied on spatial and temporal scales. Microcystis exists as a mixed population of toxic and non-toxic genotypes, and the proportion of toxic Microcystis genotypes ranged from 9.43% to 87.98%. Both Pearson correlation and stepwise multiple regressions demonstrated that throughout the entire lake, the abundances of total and toxic Microcystis and MC concns. showed significant pos. correlation with the total phosphorus and water temp., suggesting that increases in temp. together with the phosphorus concns. may promote more frequent toxic Microcystis blooms and higher concns. of MC. Whereas, dissolved inorg. carbon (DIC) was neg. correlated with the abundances of total and toxic Microcystis and MC concns., indicating that rising DIC concns. may suppress toxic Microcystis abundance and reduce the MC concns. in the future. Therefore, our results highlight the fact that future eutrophication and global climate change can affect the dynamics of toxic Microcystis blooms and hence change the MC levels in freshwater.
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      Gobler, C. J.; Burkholder, J. M.; Davis, T. W.; Harke, M. J.; Johengen, T.; Stow, C. A.; Van de Waal, D. B. The dual role of nitrogen supply in controlling the growth and toxicity of cyanobacterial blooms. Harmful Algae 2016, 54, 87– 97,  DOI: 10.1016/j.hal.2016.01.010
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      The dual role of nitrogen supply in controlling the growth and toxicity of cyanobacterial blooms
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      Harmful Algae (2016), 54 (), 87-97CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
      Historically, phosphorus (P) has been considered the primary limiting nutrient for phytoplankton assemblages in freshwater ecosystems. This review, supported by new findings from Lake Erie, highlights recent mol., lab., and field evidence that the growth and toxicity of some non-diazotrophic blooms of cyanobacteria can be controlled by nitrogen (N). Cyanobacteria such as Microcystis possess physiol. adaptations that allow them to dominate low-P surface waters, and in temperate lakes, cyanobacterial densities can be controlled by N availability. Beyond total cyanobacterial biomass, N loading has been shown to selectively promote the abundance of Microcystis and Planktothrix strains capable of synthesizing microcystins over strains that do not possess this ability. Among strains of cyanobacteria capable of synthesizing the N-rich microcystins, cellular toxin quotas have been found to depend upon exogenous N supplies. Herein, multi-year observations from western Lake Erie are presented demonstrating that microcystin concns. peak in parallel with inorg. N, but not orthophosphate, concns. and are significantly lower (p < 0.01) during years of reduced inorg. nitrogen loading and concns. Collectively, this information underscores the importance of N as well as P in controlling toxic cyanobacteria blooms. Furthermore, it supports the premise that management actions to reduce P in the absence of concurrent restrictions on N loading may not effectively control the growth and/or toxicity of non-diazotrophic toxic cyanobacteria such as the cosmopolitan, toxin-producing genus, Microcystis.
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      Van de Waal, D. B.; Verspagen, J. M. H.; Lurling, M.; Van Donk, E.; Visser, P. M.; Huisman, J. The ecological stoichiometry of toxins produced by harmful cyanobacteria: an experimental test of the carbon-nutrient balance hypothesis. Ecol. Lett. 2009, 12, 1326– 1335,  DOI: 10.1111/j.1461-0248.2009.01383.x
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      The ecological stoichiometry of toxins produced by harmful cyanobacteria: an experimental test of the carbon-nutrient balance hypothesis
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      Ecology letters (2009), 12 (12), 1326-35 ISSN:.
      The elemental composition of primary producers reflects the availability of light, carbon and nutrients in their environment. According to the carbon-nutrient balance hypothesis, this has implications for the production of secondary metabolites. To test this hypothesis, we investigated a family of toxins, known as microcystins, produced by harmful cyanobacteria. The strain Microcystis aeruginosa HUB 5-2-4, which produces several microcystin variants of different N:C stoichiometry, was cultured in chemostats supplied with various combinations of nitrate and CO(2). Excess supply of both nitrogen and carbon yielded high cellular N:C ratios accompanied by high cellular contents of total microcystin and the nitrogen-rich variant microcystin-RR. Comparable patterns were found in Microcystis-dominated lakes, where the relative microcystin-RR content increased with the seston N:C ratio. In total, our results are largely consistent with the carbon-nutrient balance hypothesis, and warn that a combination of rising CO(2) and nitrogen enrichment will affect the microcystin composition of harmful cyanobacteria.
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      Vézie, C.; Rapala, J.; Vaitomaa, J.; Seitsonen, J.; Sivonen, K. Effect of nitrogen and phosphorus on growth of toxic and nontoxic Microcystis strains and on intracellular microcystin concentrations. Microb. Ecol. 2002, 43, 443– 454,  DOI: 10.1007/s00248-001-0041-9
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      Effect of nitrogen and phosphorus on growth of toxic and nontoxic Microcystis strains and on intracellular microcystin concentrations
      Vezie, C.; Rapala, J.; Vaitomaa, J.; Seitsonen, J.; Sivonen, K.
      Microbial Ecology (2002), 43 (4), 443-454CODEN: MCBEBU; ISSN:0095-3628. (Springer-Verlag New York Inc.)
      The growth and intracellular microcystin concn. of 2 hepatotoxic and 2 nontoxic axenic Microcystis strains were measured in batch cultures with variable nitrogen (0.84-84 mg L-1) and phosphorus (0.05-5.5 mg L-1) concns. Growth was estd. by measuring dry wt., optical d., chlorophyll a, and cellular protein concn. Microcystin concns. in cells and in culture medium were measured by HPLC anal. Both nontoxic strains needed less nutrients for their growth at low nutrient concns. With high nutrient concns., the toxic strains grew better than the nontoxic strains. Growth and intracellular microcystin concn. did not correlate in the hepatotoxic strains. Multivariate regression anal. together with math. modeling revealed a significant interactive effect of nitrogen and phosphorus, which partly explains the controversial results obtained in previous studies. In this study, it was shown that variation of nitrogen and phosphorus concns. influence the growth and the microcystin prodn. of Microcystis strains and that the strains differ in their response to nutrients. High levels of nitrogen and phosphorus in freshwaters may favor the growth of toxic Microcystis strains over nontoxic ones.
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      Portmann, C.; Blom, J. F.; Gademann, K.; Juttner, F. Aerucyclamides A and B: Isolation and synthesis of toxic ribosomal heterocyclic peptides from the cyanobacterium Microcystis aeruginosa PCC 7806. J. Nat. Prod. 2008, 71, 1193– 1196,  DOI: 10.1021/np800118g
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      Aerucyclamides A and B: isolation and synthesis of toxic ribosomal heterocyclic peptides from the cyanobacterium Microcystis aeruginosa PCC 7806
      Portmann, Cyril; Blom, Judith F.; Gademann, Karl; Juttner, Friedrich
      Journal of Natural Products (2008), 71 (7), 1193-1196CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      Two new modified hexacyclopeptides, aerucyclamides A and B, were isolated from the toxic freshwater cyanobacterium M. aeruginosa PCC 7806. The constitution was assigned by spectroscopic methods, and the configuration detd. by chem. degrdn. and anal. by Marfey's method combined with chem. synthesis. Synthetic aerucyclamide B was obtained through oxidn. of aerucyclamide A (MnO2, benzene). The aerucyclamides were toxic to the freshwater crustacean Thamnocephalus platyurus, exhibiting LC50 values for congeners A and B of 30.5 and 33.8 μM, resp.
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      Chlorophyllide c (chlorophyll c) was found in axenic or unialgal cultures of 5 members of the class Xanthophyceae and in 2 members of the class Raphidophyceae (Chloromonadophyceae). Two other algae contained neither chlorophyll b nor c. One of these plants, Pleurochloris magna, is presumably a member of the class Eustigmatosphceae (Hibbard and Leedale). The other alga, clone GSB Sticho, is of uncertain systematic position. Although the xanthophyll pigments were not crit. studied, there is enough evidence to permit the conclusion that the xanthophyll suites of the chloromonads, the xanthophytes, P. magna, and clone GSB Sticho all differ in at least one respect.
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      Environmental Science & Technology (2014), 48 (4), 2097-2098CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      A method and framework for describing the identification of small mols. by high resoln. mass spectrometry (HRMS) is presented. A 5 level classification scheme was developed to indicate the proposed identification confidence levels in HRMS. The levels are confirmed structure, probable structure, substance class, unequivocal mol. formula, and exact mass of interest.
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      Stravs, M. A.; Schymanski, E. L.; Singer, H. P.; Hollender, J. Automatic recalibration and processing of tandem mass spectra using formula annotation. J. Mass Spectrom. 2013, 48, 89– 99,  DOI: 10.1002/jms.3131
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      High accuracy, high resoln. tandem mass spectrometry (MS/MS) is becoming more common in anal. applications, yet databases of these spectra remain limited. Databases require good quality spectra with sufficient compd. information, but processing, calibration, noise redn. and retrieval of compd. information are time-consuming tasks that prevent many contributions. The authors present a comprehensive workflow for the automatic processing of MS/MS using formula annotation for recalibration and cleanup to generate high quality spectra of std. compds. for upload to MassBank (www.massbank.jp). Compd. information is retrieved via Internet services. Ref. stds. of 70 pesticides were measured at various collision energies on an LTQ-Orbitrap XL to develop and evaluate the workflow. A total of 944 resulting spectra are now available on MassBank. Evidence of N adduct formation during MS/MS fragmentation processes was found, highlighting the benefits high accuracy MS/MS offers for spectral interpretation. A database of recalibrated, cleaned-up spectra resulted in the most correct spectra ranked in 1st place, regardless of whether the search spectra were recalibrated or not, whereas the av. rank of the correct mol. formula was improved from 2.55 (uncalibrated) to 1.53 when using recalibrated MS/MS data. The workflow is available as an R package RMassBank capable of generating MassBank records from raw MS and MS/MS data and can be adjusted to process data acquired with different settings and instruments. This workflow is a vital step towards addressing the need for more high quality, high accuracy MS/MS spectra in spectral databases and provides important information for spectral interpretation. Copyright © 2012 John Wiley and Sons, Ltd.
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      Nature Biotechnology (2012), 30 (10), 918-920CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      Mass spectrometry-based proteomics has become an important component of biol. research. There have been several calls for improvements and standardization of proteomics data anal. frameworks, as well as for an application programming interface for proteomics data access. In response, ProteoWizard Toolkit was developed, a robust set of opensource, software libraries and applications designed to facilitate proteomics research. With version 3.0 of the ProteoWizard Toolkit8, the challenges in the field can be mitigated through open-source, permissively licensed, cross-platform software. The Toolkit has two components: first, a suite of libraries that facilitate the development and comparison of tools for proteomics data anal. and second, a set of tools, developed using these libraries, that performs a wide array of common proteomics analyses. ProteoWizard is built upon a modular framework of many independent libraries grouped in dependency levels.
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      Martin, C.; Oberer, L.; Ino, T.; Konig, W. A.; Busch, M.; Weckesser, J. Cyanopeptolins, new depsipeptides from the cyanobacterium Microcystis sp. PCC 7806. J. Antibiot. 1993, 46, 1550– 6,  DOI: 10.7164/antibiotics.46.1550
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      Cyanopeptolins, new depsipeptides from the cyanobacterium Microcystis sp. PCC 7806
      Martin, Cornel; Oberer, Lukas; Ino, Tomio; Koenig, Wilfried A.; Busch, Michael; Weckesser, Juergen
      Journal of Antibiotics (1993), 46 (10), 1550-6CODEN: JANTAJ; ISSN:0021-8820.
      Four depsipeptides (peptide lactones), called cyanopeptolins A, B, C and D, have been isolated from the cyanobacterium Microcystis sp. PCC 7806. They possess identical structures consisting of cyclic L-glutamic acid-γ-aldehyde, L-leucine, N-methyl-phenylalanine, L-valine, L-threonine, L-aspartic acid, hexanoic acid and a variable basic amino acid. This variable amino acid can be L-arginine (cyanopeptolin A), L-lysine (cyanopeptolin B), Nε-methyl-L-lysine (cyanopeptolin C) and Nε,Nε-dimethyl-L-lysine (cyanopeptolin D), resp. The L-glutamic acid-γ-aldehyde and the amino group of L-leucine form an unusual 3-amino-6-hydroxy-2-oxo-1-piperidine system. L-Threonine is connected to L-valine via its hydroxy-group forming an ester bonding. The hexanoic acid residue is attached to the N-terminal aspartic acid residue which is not a part of the ring structure. The isolation procedure of the four cyanopeptolins as well as structure elucidation are described. Amino acid anal., GC/MS anal., FAB-MS and several NMR techniques were used to reveal the structures.
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      Bister, B.; Keller, S.; Baumann Heike, I.; Nicholson, G.; Weist, S.; Jung, G.; Sussmuth Roderich, D.; Juttner, F. Cyanopeptolin 963A, a chymotrypsin inhibitor of Microcystis PCC 7806. J. Nat. Prod. 2004, 67, 1755– 1757,  DOI: 10.1021/np049828f
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      Cyanopeptolin 963A, a chymotrypsin inhibitor of Microcystis PCC 7806
      Bister, Bojan; Keller, Simone; Baumann, Heike I.; Nicholson, Graeme; Weist, Stefan; Jung, Guenther; Suessmuth, Roderich D.; Juettner, Friedrich
      Journal of Natural Products (2004), 67 (10), 1755-1757CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
      A new depsipeptide, cyanopeptolin 963 A (I), was isolated from an axenic strain of the toxic freshwater cyanobacterium Microcystis PCC 7806. The structure of this compd. was elucidated by chem. and spectroscopic analyses, including high-resoln. ESI-FTICR-MS, 2-D NMR, and GC-MS of the hydrolyzate. The major structural difference compared to previously characterized cyanopeptolins of this strain is the replacement of the basic amino acid in position 3 by L-tyrosine. I displayed inhibitory activity against chymotrypsin with an IC50 value of 0.9 μM.
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      Downing, T. G.; Sember, C. S.; Gehringer, M. M.; Leukes, W. Medium N: P ratios and specific growth rate comodulate microcystin and protein content in Microcystis aeruginosa PCC7806 and M aeruginosa UV027. Microb. Ecol. 2005, 49, 468– 473,  DOI: 10.1007/s00248-004-0054-2
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      Medium N:P ratios and specific growth rate comodulate microcystin and protein content in Microcystis aeruginosa PCC7806 and M. aeruginosa UV027
      Downing T G; Sember C S; Gehringer M M; Leukes W
      Microbial ecology (2005), 49 (3), 468-73 ISSN:0095-3628.
      Hepatotoxin production in cyanobacteria has been shown to correlate to external stimuli such as light and nutrient concentrations and ratios, although conflicting results have been reported. Specific growth rates and protein and microcystin content of M. aeruginosa PCC7806 and M. aeruginosa UV027 were determined under nonlimiting batch culture conditions for a range of medium nitrogen and phosphorous atomic ratios. Both strains exhibited a similar optimal medium N:P ratio for increased cellular microcystin levels. Additionally, total cellular protein content and intracellular microcystin content were significantly correlated to each other (r2 = 0.81, p < 0.001). Microcystin and protein content increased considerably as the maximum specific growth rate for the experimental conditions was reached. The significant correlation of cellular protein and microcystin content and their relative increase with increasing specific growth rate, within defined ranges of medium N:P ratios, suggest a close association between microcystin production and N:P ratio-dependent assimilation of nitrogen, and resulting total cellular protein levels, which may be further modulated by specific growth rate.
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      Portmann, C.; Blom, J. F.; Kaiser, M.; Brun, R.; Juttner, F.; Gademann, K. Isolation of aerucyclamides C and D and structure revision of microcyclamide 7806A: Heterocyclic ribosomal peptides from Microcystis aeruginosa PCC 7806 and their antiparasite evaluation. J. Nat. Prod. 2008, 71, 1891– 1896,  DOI: 10.1021/np800409z
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      Isolation of aerucyclamides C and D and structure revision of microcyclamide 7806A: Heterocyclic ribosomal peptides from Microcystis aeruginosa PCC 7806 and their antiparasite evaluation
      Portmann, Cyril; Blom, Judith F.; Kaiser, Marcel; Brun, Reto; Juttner, Friedrich; Gademann, Karl
      Journal of Natural Products (2008), 71 (11), 1891-1896CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      Aerucyclamides C and D were isolated from the cyanobacterium Microcystis aeruginosa PCC 7806, and their structures were established by NMR spectroscopy and chem. transformation and degrdn. Acidic hydrolysis of aerucyclamide C (CF3CO2H, H2O) resulted in microcyclamide 7806A. This chem. evidence combined with spectroscopic and phys. data suggest a structure revision for microcyclamide 7806A, which incorporates an O-acylated Thr ammonium residue instead of the originally proposed Me oxazoline ring. The authors have prepd. microcyclamide 7806B upon basic and acidic treatment of microcyclamide 7806A, which suggests that both these compds. are hydrolysis products of aerucyclamide C and that the aerucyclamides A-D are the actual metabolites produced via ribosomal peptide synthesis in M. aeruginosa PCC 7806. Antiplasmodial evaluation established submicromolar IC50 values for aerucyclamide B against Plasmodium falciparum; low micromolar values for aerucyclamide C were found against Trypanosoma brucei rhodesiense. The compds. were selective for the parasites over a cell line of L6 rat myoblasts and are thus considered for further study as antimalarial agents.
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      Botes, D. P.; Wessels, P. L.; Kruger, H.; Runnegar, M. T. C.; Santikarn, S.; Smith, R. J.; Barna, J. C. J.; Williams, D. H. Structural studies on cyanoginosin-Lr, cyanoginosin-Yr, cyanoginosin-Ya and -cyanoginosin-Ym, peptide toxins from Microcystis aeruginosa. J. Chem. Soc., Perkin Trans. 1 1985, 2747– 2748,  DOI: 10.1039/p19850002747
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      Structural studies on cyanoginosins-LR, -YR, -YA, and -YM, peptide toxins from Microcystis aeruginosa
      Botes, Dawie P.; Wessels, Philippus L.; Kruger, Helene; Runnegar, Maria T. C.; Santikarn, Sitthivet; Smith, Richard J.; Barna, Jennifer C. J.; Williams, Dudley H.
      Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1985), (12), 2747-8CODEN: JCPRB4; ISSN:0300-922X.
      The structures of the hepatotoxins of general name cyanoginosins-XY are proposed to be cyclo-D-Ala-L-X-erythro-β-methyl-D-isoAsp-L-Y-Adda-D-isoGlu-N-methyldehydroAla, were X and Y represent variable amino acids and Adda is 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid. The structural studies on 4 variant toxins utilized NMR and mass spectral methods analogous to those recently used to det. the structure of cyanoginosin-LA.
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      Sano, T.; Kaya, K. Oscillamide-Y, a Chymotrypsin inhibitor from toxic Oscillatoria agardhii. Tetrahedron Lett. 1995, 36, 5933– 5936,  DOI: 10.1016/00404-0399(50)1198Q-
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      Oscillamide Y, a chymotrypsin inhibitor from toxic Oscillatoria agardhii
      Sano, Tomoharu; Kaya, Kunimitsu
      Tetrahedron Letters (1995), 36 (33), 5933-6CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
      Oscillamide Y (I), a chymotrypsin inhibitor, was isolated from freshwater toxic cyanobacterium Oscillatoria agardhii. The structure of I was elucidated by chem. degrdn. and 2D NMR analyses.
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      Harada, K.; Fujii, K.; Shimada, T.; Suzuki, M.; Sano, H.; Adachi, K.; Carmichael, W. W. 2 Cyclic-peptides, anabaenopeptins, a 3rd group of bioactive compounds from the cyanobacterium Anabaena flos-aquae Nrc-525-17. Tetrahedron Lett. 1995, 36, 1511– 1514,  DOI: 10.1016/0040-4039(95)00073-L
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      Two cyclic peptides, anabaenopeptins, a third group of bioactive compounds from the cyanobacterium Anabaena flos-aquae NRC 525-17
      Harada, Kenichi; Fujii, Kiyonaga; Shimada, Takayuki; Suzuki, Makoto; Sano, Hiroshi; Adachi, Kyoko; Carmichael, Wayne W.
      Tetrahedron Letters (1995), 36 (9), 1511-14CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
      Two cyclic peptides, anabaenopeptins A and B, were isolated as a 3rd group of bioactive compds. (vasodilators) from Anabaena flos-aquae NRC 525-17. Their structures were detd. by 2D-NMR techniques and Marfey's method combined with LC/MS.
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      Murakami, M.; Shin, H. J.; Matsuda, H.; Ishida, K.; Yamaguchi, K. A cyclic peptide, anabaenopeptin B, from the cyanobacterium Oscillatoria agardhii. Phytochemistry 1997, 44, 449– 452,  DOI: 10.1016/S0031-9422(96)00437-2
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      A cyclic peptide, anabaenopeptin B, from the cyanobacterium Oscillatoria agardhii
      Murakami, Masahiro; Shin, Hee Jae; Matsuda, Hisashi; Ishida, Keishi; Yamaguchi, Katsumi
      Phytochemistry (1997), 44 (3), 449-452CODEN: PYTCAS; ISSN:0031-9422. (Elsevier)
      A cyclic peptide, anabaenopeptin B (I), was isolated from the cultured cyanobacterium Oscillatoria agardhii (NIES-204). The structure of I was elucidated by extensive 2D NMR spectroscopy and chem. degrdn.
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      Di Gregorio, F. N.; Bogialli, S.; Ferretti, E.; Lucentini, L. First evidence of MC-HtyR associated to a Plankthothrix rubescens blooming in an Italian lake based on a LC-MS method for routinely analysis of twelve microcystins in freshwaters. Microchem. J. 2017, 130, 329– 335,  DOI: 10.1016/j.microc.2016.10.012
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      First evidence of MC-HtyR associated to a Plankthothrix rubescens blooming in an Italian lake based on a LC-MS method for routinely analysis of twelve microcystins in freshwaters
      Di Gregorio, F. Nigro; Bogialli, S.; Ferretti, E.; Lucentini, L.
      Microchemical Journal (2017), 130 (), 329-335CODEN: MICJAN; ISSN:0026-265X. (Elsevier B.V.)
      A recent Italian regulatory level for microcystins (MCs) in drinking water was set at 1.0 μg/L, intended as the sum of all variants that can be detd. using com. available stds. A selective multi-residue method for analyzing twelve variants of MCs (MC-RR, MC-YR, MC-LR, MC-LA, MC-LW, MC-LF, MC-LY, [D-Asp3]-MC-RR, [D-Asp3]-MC-LR, MC-WR, MC-HilR, MC-HtyR) in surface and drinking waters was optimized and validated in accordance with the Italian implementation of the Drinking Water Directive 98/83/EC. The proposed method was robust as proved by using nodularin as quality control, with inter-matrixes reproducibility better than 17% and matrix effects not significantly dependent among different water samples. LODs were in the range of 0.003-0.030 μg/L for all the analytes, allowing the quant. anal. of selected MCs at levels lower than 1/10 of the proposed new Italian parametric values. The method was tailored for the routine anal. of MCs in the frame of risk management related to MCs prodn. during toxic algal blooms. The optimized anal. protocol was then applied to the anal. of water samples collected in Occhito Lake (Apulia, Italy), used as a source of drinking water, after an extraordinary bloom of Planktothrix rubescens. In Oct. 2010, the presence of MC-HtyR was detected here with max. concn. level of 0.025 μg/L. To our knowledge, this is the first report on MC-HtyR presence, obtained with a confirmatory method, assocd. to a P. rubescens bloom in surface waters.
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      Sano, T.; Beattie, K. A.; Codd, G. A.; Kaya, K. Two (Z)-dehydrobutyrine-containing microcystins from a hepatotoxic bloom of Oscillatoria agardhii from Soulseat Loch, Scotland. J. Nat. Prod. 1998, 61, 851– 853,  DOI: 10.1021/np980047m
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      Two (Z)-dehydrobutyrine-containing microcystins from a hepatotoxic bloom of Oscillatoria agardhii from Soulseat Loch, Scotland
      Sano, Tomoharu; Beattie, Kenneth A.; Codd, Geoffrey A.; Kaya, Kunimitsu
      Journal of Natural Products (1998), 61 (6), 851-853CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society)
      Two (Z)-dehydrobutyrine (Dhb)-contg. microcystins, [D-Asp3,(Z)-Dhb7]microcystin-HtyR (I) and [D-Asp3,(Z)-Dhb7]microcystin-LR (II), were isolated from a hepatotoxic bloom of the cyanobacterium Oscillatoria agardhii from a freshwater lake in Scotland. The geometrical structure of the Dhb units in the microcystins was detd. as Z on the basis of NOE and ROESY expts.
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      Rapala, J.; Sivonen, K.; Lyra, C.; Niemela, S. I. Variation of microcystins, cyanobacterial hepatotoxins, in Anabaena spp. as a function of growth stimuli. Appl. Environ. Microbiol. 1997, 63, 2206– 2212,  DOI: 10.1128/AEM.63.6.2206-2212.1997
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      Variation of microcystins, cyanobacterial hepatotoxins, in Anabaena spp. as a function of growth stimuli
      Rapala, Jarkko; Sivonen, Kaarina; Lyra, Christina; Niemela, Seppo I.
      Applied and Environmental Microbiology (1997), 63 (6), 2206-2212CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
      Cyanobacterial hepatotoxins, microcystins, are specific inhibitors of serine/threonine protein phosphatases and potent tumor promoters. They have caused several poisonings of animals and also pose a health hazard for humans through the use of water for drinking and recreation. Different strains of the same cyanobacterial species may variously be nontoxic, be neurotoxic, or produce several microcystin variants. It is poorly understood how the amt. of toxins varies in a single strain. This lab. study shows the importance of external growth stimuli in regulating the levels and relative proportions of different microcystin variants in 2 strains of filamentous, N2-fixing Anabaena spp. The concn. of the toxins in the cells increased with P. High temps. (25-30°), together with the highest levels of light studied (test range, 2-100 μmol/m2-s), decreased their amt. Different structural variants of microcystins responded differently to growth stimuli. Variants of microcystin (MCYST)-LR correlated with temps. <25° and those of MCYST-RR correlated with higher temps. N added to the growth medium and increasing temps. increased the proportion of microcystin variants demethylated in amino acid 3. All variants remained mostly intracellular. Time was the most important factor causing the release of the toxins into the growth medium. Time, N added to the growth medium, and light fluxes >25 μmol/m2-s significantly increased the concns. of dissolved toxins. It thus seems that the redn. of P loads in bodies of water might play a role in preventing the health hazards that toxic cyanobacterial water blooms pose, not only by decreasing the cyanobacteria but also by decreasing their toxin content.
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    56. 56
      Wiedner, C.; Visser, P. M.; Fastner, J.; Metcalf, J. S.; Codd, G. A.; Mur, L. R. Effects of light on the microcystin content of Microcystis strain PCC 7806. Appl. Environ. Microbiol. 2003, 69, 1475– 1481,  DOI: 10.1128/AEM.69.3.1475-1481.2003
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      Effects of light on the microcystin content of Microcystis strain PCC 7806
      Wiedner, Claudia; Visser, Petra M.; Fastner, Jutta; Metcalf, James S.; Codd, Geoffrey A.; Mur, Luuc R.
      Applied and Environmental Microbiology (2003), 69 (3), 1475-1481CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
      Many cyanobacteria produce microcystins, hepatotoxic cyclic heptapeptides that can affect animals and humans. The effects of photosynthetically active radiation (PAR) on microcystin prodn. by Microcystis strain PCC 7806 were studied in continuous cultures. Microcystis strain PCC 7806 was grown under PAR intensities between 10 and 403 μmol of photons m-2 s-1 on a light-dark rhythm of 12 h-12 h. The microcystin concn. per cell, per unit biovolume and protein, was estd. under steady-state and transient-state conditions and on a diurnal timescale. The cellular microcystin content varied between 34.5 and 81.4 fg cell-1 and was significantly pos. correlated with growth rate under PAR-limited growth but not under PAR-satd. growth. Microcystin prodn. and PAR showed a significant pos. correlation under PAR-limited growth and a significant neg. correlation under PAR-satd. growth. The microcystin concn., as a ratio with respect to biovolume and protein, correlated neither with growth rate nor with PAR. Adaptation of microcystin prodn. to a higher irradiance during transient states lasted for 5 days. During the period of illumination at a PAR of 10 and 40 μmol of photons m-2 s-1, the intracellular microcystin content increased to values 10 to 20% higher than those at the end of the dark period. Extracellular (dissolved) microcystin concns. were 20 times higher at 40 μmol of photons m-2 s-1, than at 10 μmol of photons m-2 s-1 and did not change significantly during the light-dark cycles at both irradiances. In summary, our results showed a pos. effect of PAR on microcystin prodn. and content of Microcystis strain PCC 7806 up to the point where the max. growth rate is reached, while at higher irradiances the microcystin prodn. is inhibited.
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      Saxton, M. A.; Arnold, R.; Bourbonniere, R. A.; McKay, R. M. L.; Wilhelm, S. W. Plasticity of total and intracellular phosphorus quotas in Microcystis aeruginosa cultures and Lake Erie algal assemblages. Front. Microbiol. 2012, 3, 3  DOI: 10.3389/fmicb.2012.00003
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      Plasticity of total and intracellular phosphorus quotas in Microcystis aeruginosa cultures and Lake Erie algal assemblages
      Saxton, Matthew A.; Arnold, Robert J.; Bourbonniere, Richard A.; McKay, Robert Michael L.; Wilhelm, Steven W.
      Frontiers in Aquatic Microbiology (2012), 3 (Jan.), 3CODEN: FAMRCY ISSN:. (Frontiers Media S.A.)
      Blooms of the potentially toxic cyanobacterium Microcystis are common events globally, and as a result significant resources continue to be dedicated to monitoring and controlling these events. Recent studies have shown that a significant proportion of total cell-assocd. phosphorus (P) in marine phytoplankton can be surface adsorbed; as a result studies completed to date do not accurately report the P demands of these organisms. In this study, we measure the total cell-assocd. and intracellular P as well as growth rates of two toxic strains of Microcystis aeruginosa Kutz grown under a range of P concns. The results show that the intracellular P pool in Microcystis represents a percentage of total cell-assocd. P (50-90 %) similar to what has been reported for actively growing algae in marine systems. Intracellular P concns. (39-147 fg cell-1) generally increased with increasing P concns. in the growth medium, but growth rate and the ratio of total cell-assocd. to intracellular P remained generally stable. Intracellular P quotas and growth rates in cells grown under the different P treatments illustrate the ability of this organism to successfully respond to changes in ambient P loads, and thus have implications for ecosystem scale productivity models employing P concns. to predict algal bloom events.
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      Kuniyoshi, T. M.; Sevilla, E.; Bes, M. T.; Fillat, M. F.; Peleato, M. L. Phosphate deficiency (N/P 40:1) induces mcyD transcription and microcystin synthesis in Microcystis aeruginosa PCC7806. Plant Physiol. Biochem. 2013, 65, 120– 124,  DOI: 10.1016/j.plaphy.2013.01.011
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      Phosphate deficiency (N/P 40:1) induces mcyD transcription and microcystin synthesis in Microcystis aeruginosa PCC7806
      Kuniyoshi, Tais M.; Sevilla, Emma; Bes, M. Teresa; Fillat, Maria F.; Peleato, M. Luisa
      Plant Physiology and Biochemistry (Issy-les-Moulineaux, France) (2013), 65 (), 120-124CODEN: PPBIEX; ISSN:0981-9428. (Elsevier Masson SAS)
      A real-time RT-PCR anal. of the transcriptional response to phosphate availability of the mcyD gene and microcystin-LR synthesis in Microcystis aeruginosa PCC7806 revealed that no significant changes were obsd. in the relative quantification of mcyD under excess phosphate (N/P = 1:1), whereas in deficiency of this nutrient (N/P = 40:1), a steady increase of mcyD during the exponential growth phase was detected, showing a maximal level on the 7th day of growth with a 6.8-fold increase over the control cells. The microcystin content in phosphate deficient cells correlates with the trend of mcyD transcription obsd. Also, the authors demonstrate that under phosphate deficiency conditions with a ratio of 40:1 N/P, the growth of M. aeruginosa PCC7806 was not affected when compared to control and phosphate excess samples. When blooms occur, the nutrients become exhausted and therefore phosphate availability will be scarce. In such a complex scenario, microcystin synthesis could be a response to phosphate deficiency, among other stress parameters.
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      Krüger, T.; Holzel, N.; Luckas, B. Influence of cultivation parameters on growth and microcystin production of Microcystis aeruginosa (cyanophyceae) isolated from Lake Chao (China). Microb. Ecol. 2012, 63, 199– 209,  DOI: 10.1007/s00248-011-9899-3
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      Jähnichen, S.; Long, B. M.; Petzoldt, T. Microcystin production by Microcystis aeruginosa: Direct regulation by multiple environmental factors. Harmful Algae 2011, 12, 95– 104,  DOI: 10.1016/j.hal.2011.09.002
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      Watanabe, M. F.; Harada, K. I.; Matsuura, K.; Watanabe, M.; Suzuki, M. Heptapeptide toxin production during the batch culture of two Microcystis species (cyanobacteria). J. Appl. Phycol. 1989, 1, 161– 165,  DOI: 10.1007/BF00003879
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      Jankowiak, J.; Hattenrath-Lehmann, T.; Kramer, B. J.; Ladds, M.; Gobler, C. J. Deciphering the effects of nitrogen, phosphorus, and temperature on cyanobacterial bloom intensification, diversity, and toxicity in western Lake Erie. Limnol. Oceanogr. 2019, 64, 1347– 1370,  DOI: 10.1002/lno.11120
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      Deciphering the effects of nitrogen, phosphorus, and temperature on cyanobacterial bloom intensification, diversity, and toxicity in western Lake Erie
      Jankowiak, Jennifer; Hattenrath-Lehmann, Theresa; Kramer, Benjamin J.; Ladds, Megan; Gobler, Christopher J.
      Limnology and Oceanography (2019), 64 (3), 1347-1370CODEN: LIOCAH; ISSN:0024-3590. (John Wiley & Sons, Inc.)
      Although cyanobacterial harmful algal blooms (CHABs) are promoted by nutrient loading and elevated temps., the effects of these processes on bloom diversity are unclear. This study used traditional and next-generation sequencing approaches to assess shifts in phytoplankton, cyanobacterial (16S rRNA), and microcystin-producing (mcyE) communities during CHABs in western Lake Erie (Maumee and Sandusky Bays) in response to natural and exptl. gradients of nitrogen (N), phosphorus (P), and temp. CHABs were most intense near the Maumee and Sandusky Rivers and were dominated by Microcystis and Planktothrix, resp. Sequencing of 16S amplicons revealed cryptic cyanobacterial diversity (47 genera) including high abundances of two distinct clades of Synechococcus in both bays and significant differences in community structure between nutrient-rich nearshore sites and less eutrophic offshore sites. Sequencing of mcyE genes revealed low taxonomic (n = 3) but high genetic diversity (n = 807), with toxigenic strains of Planktothrix being more abundant than Microcystis and more closely paralleling microcystin concns. Cyanobacterial abundance significantly increased in response to elevated N, with the greatest increases in combined high N, P, and temp. treatments that concurrently suppressed green and brown algae. N significantly increased microcystin concns. and the relative abundance of nondiazotrophic genera such as Planktothrix, while diazotrophic genera such as Dolichospermum and Aphanizomenon were, in some cases, enhanced by high P and temp. While nutrients and elevated temps. promote CHABs, differing combinations selectively promote individual cyanobacterial genera and strains, indicating management of both N and P will be required to control all cyanobacteria in Lake Erie, particularly as lake temps. rise.
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      Harke, M. J.; Davis, T. W.; Watson, S. B.; Gobler, C. J. Nutrient-controlled niche differentiation of western Lake Erie cyanobacterial populations revealed via metatranscriptomic surveys. Environ. Sci. Technol. 2016, 50, 604– 615,  DOI: 10.1021/acs.est.5b03931
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      Nutrient-Controlled Niche Differentiation of Western Lake Erie Cyanobacterial Populations Revealed via Metatranscriptomic Surveys
      Harke, Matthew J.; Davis, Timothy W.; Watson, Susan B.; Gobler, Christopher J.
      Environmental Science & Technology (2016), 50 (2), 604-615CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      Although toxic cyanobacterial blooms in western Lake Erie threaten drinking water supplies and are promoted by nutrient loading, the precise nutrient regime that selects specific cyanobacteria populations is poorly understood. We assess shifts in cyanobacterial abundances and global gene-expression patterns in response to natural and manipulated gradients in N and P to identify gene pathways that facilitate dominance by different cyanobacteria. Gradients in sol. reactive phosphorus shaped cyanobacterial communities and elicited the largest transcriptomic responses. Under high-P conditions (closest to the mouth of the Maumee River), Anabaena and Planktothrix were the dominant cyanobacterial populations, and exptl. P and ammonium enrichment promoted N fixation gene (nifH) expression in Anabaena. For Microcystis, exptl. addns. of P up-regulated genes involved in phage defense, genomic rearrangement, and nitrogen acquisition but led to lower abundances. Within offshore, low-P regions of the western basin of Lake Erie, Microcystis up-regulated genes assocd. with P scavenging (pstSCAB, phoX) and dominated cyanobacterial communities. Exptl. addns. of ammonium and urea did not alter Microcystis abundances but did up-regulate protease inhibitors (aer and mcn gene sets) and microcystin synthetase genes (mcy), with urea enrichment yielding significant increases in microcystin concns. Our findings suggest that management plans that reduce P loads alone may not significantly reduce the risk of cyanobacterial blooms in western Lake Erie but rather may promote a shift among cyanobacterial populations (Microcystis, Anabaena, and Planktothrix) toward a greater dominance by toxic strains of Microcystis.
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    64. 64
      Wan, L. L.; Chen, X. Y.; Deng, Q. H.; Yang, L.; Li, X. W.; Zhang, J. Y.; Song, C. L.; Zhou, Y. Y.; Cao, X. Y. Phosphorus strategy in bloom-forming cyanobacteria (Dolichospermum and Microcystis) and its role in their succession. Harmful Algae 2019, 84, 46– 55,  DOI: 10.1016/j.hal.2019.02.007
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      Phosphorus strategy in bloom-forming cyanobacteria (Dolichospermum and Microcystis) and its role in their succession
      Wan, Lingling; Chen, Xiaoyan; Deng, Qinghui; Yang, Liu; Li, Xiaowen; Zhang, Junyi; Song, Chunlei; Zhou, Yiyong; Cao, Xiuyun
      Harmful Algae (2019), 84 (), 46-55CODEN: HAALDD; ISSN:1568-9883. (Elsevier B.V.)
      Dolichospermum (formerly Anabaena) and Microcystis cause harmful cyanobacterial blooms in freshwater ecosystems worldwide. Input redn. of both nitrogen (N) and phosphorus (P) are commonly recognized as basic ways of controlling blooms, but little is known about the roles of nutrients and their using strategy among cyanobacteria in triggering the succession of diazotrophic to non-diazotrophic cyanobacteria. In this study, we investigated in situ responses of cyanobactria to ambient P status during the transition from Dolichospermum flos-aquae to Microcystis spp. in Lake Taihu and Lake Chaohu. While dominant in phytoplankton community, D. flos-aquae experienced P deficiency as evidenced by qual. detection of extracellular phosphatase via enzyme labeled fluorescence (ELF). The percentage of ELF-labeled D. flos-aquae cells was 33% when it dominated the phytoplankton community, and was 78% when it co-dominated with Microcystis spp., indicating an increase in P deficiency. Meanwhile, no ELF-labeled Microcystis cells were obsd. while polyphosphate body (PPB) were present, suggesting that Microcystis spp. were not P deficient. Addnl., the percentages of Microcystis cells contg. PPB showed an inverted "U-shaped" relationship with concns. on sol. reactive phosphorus (SRP). To validate the field observation, a lab. study of the monocultures of the dominant cyanobacteria was conducted. Extracellular alk. phosphatase activity (APA) and PPB accumulation were regulated by P availability in monocultures of D. flos-aquae. Interestingly, no cell bound extracellular phosphatase was found on Microcystis aeruginasa even in the culture without P supply. Consistently, the expressions of phosphatase encoding gene phoX showed no differences among the treatments. The way in which PPB accumulation occurred in Microcystis spp. in response to P availability in the cultures was similar to that obsd. in the field, demonstrating a strategy of energy conservation over P accumulation. The competitive advantage of Microcystis spp. was displayed at low P concns.: where it could rapidly uptake and store inorg. P, which also increased the P deficiency of the coexisting phytoplankton species. Responses of P-transport gene pstS confirmed this hypothesis. The physiol. and mol. mechanisms mentioned above enable Microcystis to survive and proliferate in environment with low available P supply more efficiently. In conclusion, different cyanobacterial species have distinct ways of responding to P availability, suggesting that the control of cyanobacterial blooms by targeted nutrient redn. is largely dependent upon the dominant species. P redn. is more effective in controlling diazotrophic cyanobacteria than non-diazotrophic cyanobacteria.
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      Facey, J. A.; Apte, S. C.; Mitrovic, S. M. A Review of the effect of trace metals on freshwater cyanobacterial growth and toxin production. Toxins 2019, 11, 643  DOI: 10.3390/toxins11110643
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      Long, B. M.; Jones, G. J.; Orr, P. T. Cellular microcystin content in N-limited Microcystis aeruginosa can be predicted from growth rate. Appl. Environ. Microbiol. 2001, 67, 278– 283,  DOI: 10.1128/AEM.67.1.278-283.2001
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      Cellular microcystin content in N-limited Microcystis aeruginosa can be predicted from growth rate
      Long, Benedict M.; Jones, Gary J.; Orr, Philip T.
      Applied and Environmental Microbiology (2001), 67 (1), 278-283CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
      Cell quotas of microcystin (QMCYST; femtomoles of MCYST per cell), protein, and chlorophyll a (Chl a), cell dry wt., and cell vol. were measured over a range of growth rates in N-limited chemostat cultures of the toxic cyanobacterium Microcystis aeruginosa MASH 01-A19. There was a pos. linear relationship between QMCYST and specific growth rate (μ), from which we propose a generalized model that enables QMCYST at any nutrient-limited growth rate to be predicted based on a single batch culture expt. The model predicts QMCYST from μ, μmax (max. specific growth rate), QMCYSTmax (max. cell quota), and QMCYSTmin (min. cell quota). Under the conditions examd. in this study, we predict a QMCYSTmax of 0.129 fmol cell-1 at μmax and a QMCYSTmin of 0.050 fmol cell-1 at μ = 0. Net MCYST prodn. rate (RMCYST) asymptotes to zero at μ = 0 and reaches a max. of 0.155 fmol cell-1 day-1 at μmax. MCYST/dry wt. ratio (milligrams per g [dry wt.]) increased linearly with μ, whereas the MCYST/protein ratio reached a max. at intermediate μ. In contrast, the MCYST/Chl a ratio remained const. Cell vol. correlated neg. with μ, leading to an increase in intracellular MCYST concn. at high μ. Taken together, our results show that fast-growing cells of N-limited M. aeruginosa are smaller, are of lower mass, and have a higher intracellular MCYST quota and concn. than slow-growing cells. The data also highlight the importance of detg. cell MCYST quotas, as potentially confusing interpretations can arise from detg. MCYST content as a ratio to other cell components.
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    67. 67
      Horst, G. P.; Sarnelle, O.; White, J. D.; Hamilton, S. K.; Kaul, R. B.; Bressie, J. D. Nitrogen availability increases the toxin quota of a harmful cyanobacterium, Microcystis aeruginosa. Water Res. 2014, 54, 188– 198,  DOI: 10.1016/j.watres.2014.01.063
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      Nitrogen availability increases the toxin quota of a harmful cyanobacterium, Microcystis aeruginosa
      Horst, Geoffrey P.; Sarnelle, Orlando; White, Jeffrey D.; Hamilton, Stephen K.; Kaul, Raj Reni B.; Bressie, Julianne D.
      Water Research (2014), 54 (), 188-198CODEN: WATRAG; ISSN:0043-1354. (Elsevier Ltd.)
      An important objective in understanding harmful phytoplankton blooms is detg. how environmental factors influence the toxicity of bloom-forming species. We examd. how nutrients and grazers (dreissenid mussels) affect the prodn. of microcystin (a liver toxin) by the cyanobacterium Microcystis aeruginosa, via a combination of field and lab. expts., and field observations in Lake Erie. The field expt. revealed no effect of mussel d. on microcystin quota (particulate microcystin per unit Microcystis biomass). In contrast, in both field and lab. expts., nitrogen-limited conditions led to substantially reduced microcystin quota relative to phosphorus-limited or nutrient-satd. conditions. In the field expt., microcystin per unit of mcyB gene was strongly reduced under nitrogen-limited conditions, indicating a phenotypic response. Results from a seasonal survey in the western basin of Lake Erie revealed a similar neg. influence of nitrogen limitation (as indexed by nitrate concn.) on microcystin quota. Our results are consistent with stoichiometric considerations in that the cell quota of a nitrogen-rich secondary metabolite, microcystin, was reduced disproportionately under nitrogen limitation.
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      Tillett, D.; Dittmann, E.; Erhard, M.; von Döhren, H.; Borner, T.; Neilan, B. A. Structural organization of microcystin biosynthesis in Microcystis aeruginosa PCC7806: an integrated peptide-polyketide synthetase system. Chem. Biol. 2000, 7, 753– 764,  DOI: 10.1016/S1074-5521(00)00021-1
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      Structural organization of microcystin biosynthesis in Microcystis aeruginosa PCC7806: an integrated peptide-polyketide synthetase system
      Tillett, Daniel; Dittmann, Elke; Erhard, Marcel; Von Dohren, Hans; Borner, Thomas; Neilan, Brett A.
      Chemistry & Biology (2000), 7 (10), 753-764CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Science Ltd.)
      Blooms of toxic cyanobacteria (blue-green algae) have become increasingly common in the surface waters of the world. Of the known toxins produced by cyanobacteria, the microcystins are the most significant threat to human and animal health. These cyclic peptides are potent inhibitors of eukaryotic protein phosphatases type 1 and 2A. Synthesized nonribosomally, the microcystins contain a no. of unusual amino acid residues including the β-amino polyketide moiety Adda (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadienoic acid). We have characterized the microcystin biosynthetic gene cluster from Microcystis aeruginosa PCC7806. A cluster spanning 55 kb, composed of 10 bidirectionally transcribed open reading frames arranged in two putative operons (mcyA-C and mcyD-J), has been correlated with microcystin formation by gene disruption and mutant anal. Of the 48 sequential catalytic reactions involved in microcystin synthesis, 45 have been assigned to catalytic domains within six large multienzyme synthases/synthetases (McyA-E, G), which incorporate the precursors phenylacetate, malonyl-CoA, S-adenosyl-L-methionine, glutamate, serine, alanine, leucine, D-methyl-isoaspartate, and arginine. The addnl. four monofunctional proteins are putatively involved in O-methylation (McyJ), epimerization (McyF), dehydration (Mcyl), and localization (McyH). The unusual polyketide amino acid Adda is formed by transamination of a polyketide precursor as enzyme-bound intermediate, and not released during the process. This report is the first complete description of the biosynthesis pathway of a complex cyanobacterial metabolite. The enzymic organization of the microcystin assembly represents an integrated polyketide-peptide biosynthetic pathway with a no. of unusual structural and enzymic features. These include the integrated synthesis of a β-amino-pentaketide precursor and the formation of β- and γ-carboxyl-peptide bonds, resp. Other features of this complex system also obsd. in diverse related biosynthetic clusters are integrated C- and N-methyltransferases, an integrated aminotransferase, and an assocd. O-methyltransferase and a racemase acting on acidic amino acids.
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