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Cytotoxic Lipopeptide Muscotoxin A, Isolated from Soil Cyanobacterium Desmonostoc muscorum, Permeabilizes Phospholipid Membranes by Reducing Their Fluidity

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Department of Phototrophic Microorganisms−Algatech, Institute of Microbiology, Academy of Sciences of the Czech Republic, Opatovický mlýn, 379 81 Třeboň, Czech Republic
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, 85 Park Road, 1023 Auckland, New Zealand
§ Faculty of Science, Institute of Chemistry, University of South Bohemia, Branišovská 1760, 370 05 České Budějovice, Czech Republic
Laboratory of Molecular Structure Characterization, Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague, Czech Republic
Department of Biophysical Chemistry, J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Dolejškova 2155/3, 182 23 Prague 8, Czech Republic
# Department of Genetics and Microbiology, Faculty of Sciences, Charles University, Viničná 5, 128 44 Prague 2, Czech Republic
Department of Cell Biology, Faculty of Sciences, Charles University, Viničná 7, 128 00 Prague 2, Czech Republic
Department of Biochemistry, Faculty of Sciences, Charles University, Hlavova 8, 128 40 Prague, Czech Republic
Department of Analytical Chemistry, Institute of Chemical Technology, Technická 5, 166 28 Dejvice, Prague, Czech Republic
Institute of Entomology, Biology Centre, Academy of Sciences of the Czech Republic, v.v.i., 370 05 České Budějovice, Czech Republic
Cite this: Chem. Res. Toxicol. 2015, 28, 2, 216–224
Publication Date (Web):January 26, 2015
https://doi.org/10.1021/tx500382b
Copyright © 2015 American Chemical Society

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    Abstract

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    There is mounting evidence that cyanobacterial lipopeptides can kill mammalian cells, presenting a hazard to human health. Unfortunately, their mechanism of toxicity is poorly understood. We have isolated new cyclic undeca-lipopeptides muscotoxin A and B containing unique lipophilic residue 3-amino-2,5-dihydroxydecanoic acid (5-OH Ahdoa). Muscotoxin B was not used for biological studies due to its poor yield. Muscotoxin A was cytotoxic to YAC-1, Sp/2, and HeLa cancer cell lines (LC50 ranged from 9.9 to 13.2 μM after 24 h of exposure), causing membrane damage and influx of calcium ions. Subsequently, we studied this lytic mechanism using synthetic liposomes with encapsulated fluorescent probes. Muscotoxin A permeabilized liposomes composed exclusively of phospholipids, demonstrating that no proteins or carbohydrates present in biomembranes are essential for its activity. Paradoxically, the permeabilization activity of muscotoxin A was mediated by a significant reduction in membrane surface fluidity (stiffening), the opposite of that caused by synthetic detergents and cytolytic lipopeptide puwainaphycin F. At 25 °C, muscotoxin A disrupted liposomes with and without cholesterol/sphingomyelin; however, at 37 °C, it was selective against liposomes with cholesterol/sphingomyelin. It appears that both membrane fluidity and organization can affect the lytic activity of muscotoxin A. Our findings strengthen the evidence that cyanobacterial lipopeptides specifically disrupt mammalian cell membranes and bring new insights into the mechanism of this effect.

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    Table S1: 1H and 13C NMR data of muscotoxin A1. Table S2: 1H and 13C NMR data of muscotoxin A2. Figure S1: 1H NMR spectrum of muscotoxin A. Figure S2: 1H NMR spectrum of muscotoxin B. Figure S3: HSQC spectrum of aliphatic region of muscotoxin A. Figure S4: HSQC spectrum of aliphatic region of muscotoxin B. Figure S5: HMBC spectrum of carbonyl carbon correlations used for muscotoxin A amino acid sequence determination. Figure S6: HMBC spectrum of carbonyl carbon correlations used for muscotoxin B amino acid sequence determination. Figure S7: Fragmentation spectrum of muscotoxin A. Figure S8: Steady-state emission spectra of Patman fluorescent probe embedded in liposomes 2 treated with microcystin-LR (MCLR) and cyclosporin A (CsA) at 25 °C. Figure S9. Steady-state emission spectra of Patman fluorescent probe embedded in liposomes 2 treated with 0.1 and 1% synthetic detergents Triton X-100, Octyl glucoside, CHAPS, and Tween20 at 25 °C. This material is available free of charge via the Internet at http://pubs.acs.org.

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