ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Structures of Five Components of the Actinomycin Z Complex from Streptomycesfradiae, Two of Which Contain 4-Chlorothreonine

View Author Information
Institut für Organische Chemie, Georg-August-Universität Göttingen, D-37077 Göttingen, Germany, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0820, and Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-7448
Cite this: J. Nat. Prod. 2000, 63, 3, 352–356
Publication Date (Web):February 12, 2000
Copyright © 2000 American Chemical Society and American Society of Pharmacognosy

    Article Views





    Other access options
    Supporting Info (1)»


    Structure elucidation of five components of the actinomycin Z complex (Z1−Z5) isolated from Streptomycesfradiae is described. The components were separated by Si gel column chromatography and TLC/PLC and analyzed by ESIMS, FABMS, LC−MS of derivatized hydrolysates, and 2D NMR techniques. This permitted determination of the complete structures of actinomycins Z1−Z5. In Z3 and Z5, site 1 of the β-depsipeptide is occupied by the rare 4-chloro-l-threonine, an amino acid not previously found in an actinomycin. The structural variants of the actinomycin Z complex have the molecular architecture typical of other actinomycins but possess greater structural diversity resulting from the presence of several highly unusual amino acids. Actinomycins Z3 and Z5, but not Z1, were more potent than actinomycin D in cytotoxicity assays against three tumor cell lines.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

     Institut für Organische Chemie, Georg-August-Universität Göttingen.

     Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases, NIH.


     To whom correspondence should be addressed. Tel.:  (301) 435-9156. Fax:  (301) 480-4817. E-mail:  [email protected].


     Developmental Therapeutics Program, National Cancer Institute, NIH.

    Supporting Information Available

    Jump To

    2D NMR connectivity diagrams (TOCSY and NOESY) for actinomycins Z1 and Z5 and linked-scan FABMS data (analogous to Table 5) for actinomycins Z1−Z4. This information is available on the World Wide Web at

    Terms & Conditions

    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:

    Cited By

    This article is cited by 31 publications.

    1. Yern-Hyerk Shin, Yeon Hee Ban, Jisu Shin, In Wook Park, Soljee Yoon, Keebeom Ko, Jongheon Shin, Sang-Jip Nam, Jaclyn M. Winter, YoungSoo Kim, Yeo Joon Yoon, Dong-Chan Oh. Azetidine-Bearing Non-Ribosomal Peptides, Bonnevillamides D and E, Isolated from a Carrion Beetle-Associated Actinomycete. The Journal of Organic Chemistry 2021, 86 (16) , 11149-11159.
    2. Wenlong Cai, Xiachang Wang, Sherif I. Elshahawi, Larissa V. Ponomareva, Xiaodong Liu, Matthew R. McErlean, Zheng Cui, Ashley L. Arlinghaus, Jon S. Thorson, and Steven G. Van Lanen . Antibacterial and Cytotoxic Actinomycins Y6–Y9 and Zp from Streptomyces sp. Strain Gö-GS12. Journal of Natural Products 2016, 79 (10) , 2731-2739.
    3. Jens Bitzer,, Victoria Gesheva, and, Axel Zeeck. Actinomycins with Altered Threonine Units in the β-Peptidolactone. Journal of Natural Products 2006, 69 (8) , 1153-1157.
    4. Adebimpe Adesina, Rachid Skouta. Diversity-Orientated Synthesis and Biological Properties of Compounds Based on the N-Phenylquinoneimine Scaffold. Molecules 2024, 29 (1) , 249.
    5. Wanzhu Zhao, Guangfei Wang, Lin Guo, Jingmin Wang, Congcong Jing, Ben Liu, Feng Zhao, Shumin Zhang, Zeping Xie. Asp-containing actinomycin and tetracyclic chromophoric analogues from the Streptomyces sp. strain S22. Organic & Biomolecular Chemistry 2023, 21 (8) , 1737-1743.
    6. Meixi He, Yi Wang, Shuai Huang, Nan Zhao, Mengchun Cheng, Xiaozhe Zhang. Computational exploration of natural peptides targeting ACE2. Journal of Biomolecular Structure and Dynamics 2022, 40 (17) , 8018-8029.
    7. Ahila P. Devi, Gnanasing L. Jesumaharaja, Keerthana Balasundaram, Nandita Sahana, Pratik M. Battacharya, Ayon Roy, Sekhar Bandyopadhyay, Surajit Khalko. Streptomyces sp.: a feasible biocontrol agent for sustainable management of crop diseases. 2022, 377-388.
    8. Kamal A. Qureshi, Avinash D. Bholay, Pankaj K. Rai, Hamdoon A. Mohammed, Riaz A. Khan, Faizul Azam, Mariusz Jaremko, Abdul-Hamid Emwas, Piotr Stefanowicz, Mateusz Waliczek, Monika Kijewska, Ehab A. Ragab, Medhat Rehan, Gamal O. Elhassan, Md Jamir Anwar, Dinesh K. Prajapati. Isolation, characterization, anti-MRSA evaluation, and in-silico multi-target anti-microbial validations of actinomycin X2 and actinomycin D produced by novel Streptomyces smyrnaeus UKAQ_23. Scientific Reports 2021, 11 (1)
    9. Qin-Pei Lu, Yong-Mei Huang, Shao-Wei Liu, Gang Wu, Qin Yang, Li-Fang Liu, Hai-Tao Zhang, Yi Qi, Ting Wang, Zhong-Ke Jiang, Jun-Jie Li, Hao Cai, Xiu-Jun Liu, Hui Luo, Cheng-Hang Sun. Metabolomics Tools Assisting Classic Screening Methods in Discovering New Antibiotics from Mangrove Actinomycetia in Leizhou Peninsula. Marine Drugs 2021, 19 (12) , 688.
    10. Ram Hari Dahal, Tuan Manh Nguyen, Ramesh Prasad Pandey, Tokutaro Yamaguchi, Jae Kyung Sohng, Jongsung Noh, Seung-Woon Myung, Jaisoo Kim. The genome insights of Streptomyces lannensis T1317-0309 reveals actinomycin D production. The Journal of Antibiotics 2020, 73 (12) , 837-844.
    11. Liwen Bai, Pian Chen, Jiangxia Xiang, Jiarui Sun, Xinxiang Lei. Enantiomeric NMR discrimination of carboxylic acids using actinomycin D as a chiral solvating agent. Organic & Biomolecular Chemistry 2019, 17 (6) , 1466-1470.
    12. Ivana Crnovčić, Manuel Lang, Ingo Ortel, Roderich D. Süssmuth, Ullrich Keller. Comparison of actinomycin peptide synthetase formation in Streptomyces chrysomallus and Streptomyces antibioticus. Journal of Basic Microbiology 2019, 59 (2) , 148-157.
    13. Miao Dong, Pei Cao, Ya-Tuan Ma, Jianying Luo, Yijun Yan, Rong-Tao Li, Sheng-Xiong Huang. A new actinomycin Z analogue with an additional oxygen bridge between chromophore and β -depsipentapeptide from Streptomyces sp. KIB-H714. Natural Product Research 2019, 33 (2) , 219-225.
    14. Wei-Hua Jiao, Wei Yuan, Zhi-Yong Li, Jing Li, Lei Li, Jia-Bao Sun, Yu-Han Gui, Jie Wang, Bo-Ping Ye, Hou-Wen Lin. Anti-MRSA actinomycins D1-D4 from the marine sponge-associated Streptomyces sp. LHW52447. Tetrahedron 2018, 74 (40) , 5914-5919.
    15. Siamak Semsary, Ivana Crnovčić, Ronja Driller, Joachim Vater, Bernhard Loll, Ullrich Keller. Ketonization of Proline Residues in the Peptide Chains of Actinomycins by a 4‐Oxoproline Synthase. ChemBioChem 2018, 19 (7) , 706-715.
    16. Qiang Wang, Yixuan Zhang, Mian Wang, Yi Tan, Xinxin Hu, Hongwei He, Chunling Xiao, Xuefu You, Yiguang Wang, Maoluo Gan. Neo-actinomycins A and B, natural actinomycins bearing the 5H-oxazolo[4,5-b]phenoxazine chromophore, from the marine-derived Streptomyces sp. IMB094. Scientific Reports 2017, 7 (1)
    17. Antonella Scaglione, Maria Rosaria Fullone, Linda Celeste Montemiglio, Giacomo Parisi, Carlotta Zamparelli, Beatrice Vallone, Carmelinda Savino, Ingeborg Grgurina. Structure of the adenylation domain Thr1 involved in the biosynthesis of 4‐chlorothreonine in Streptomyces sp. OH ‐5093—protein flexibility and molecular bases of substrate specificity. The FEBS Journal 2017, 284 (18) , 2981-2999.
    18. Dongyang Wang, Cong Wang, Pengyan Gui, Haishan Liu, Sameh M. H. Khalaf, Elsayed A. Elsayed, Mohammed A. M. Wadaan, Wael N. Hozzein, Weiming Zhu. Identification, Bioactivity, and Productivity of Actinomycins from the Marine-Derived Streptomyces heliomycini. Frontiers in Microbiology 2017, 8
    19. Usman Aftab, Imran Sajid. Antitumor Peptides from Streptomyces sp. SSA 13, Isolated from Arabian Sea. International Journal of Peptide Research and Therapeutics 2017, 23 (2) , 199-211.
    20. Joachim Vater, Ivana Crnovčić, Siamak Semsary, Ullrich Keller. MALDI‐TOF mass spectrometry, an efficient technique for in situ detection and characterization of actinomycins. Journal of Mass Spectrometry 2014, 49 (3) , 210-222.
    21. Maria Rosaria Fullone, Alessandro Paiardini, Rossella Miele, Sara Marsango, Dennis C. Gross, Satoshi Omura, Enric Ros‐Herrera, Maria Carmela Bonaccorsi di Patti, Aldo Laganà, Stefano Pascarella, Ingeborg Grgurina. Insight into the structure–function relationship of the nonheme iron halogenases involved in the biosynthesis of 4‐chlorothreonine –  T hr3 from S treptomyces sp. OH ‐5093 and S yr B 2 from P seudomonas syringae pv. syringae B 301 DR. The FEBS Journal 2012, 279 (23) , 4269-4282.
    22. Caixia Chen, Fuhang Song, Qian Wang, Wael M. Abdel-Mageed, Hui Guo, Chengzhang Fu, Weiyuan Hou, Huanqin Dai, Xueting Liu, Na Yang, Feng Xie, Ke Yu, Ruxian Chen, Lixin Zhang. A marine-derived Streptomyces sp. MS449 produces high yield of actinomycin X2 and actinomycin D with potent anti-tuberculosis activity. Applied Microbiology and Biotechnology 2012, 95 (4) , 919-927.
    23. Bojidarka Ivanova, Michael Spiteller. Coordination ability of silver(I) with antimycins and actinomycins – Properties of the T-shaped chromophores. Polyhedron 2012, 38 (1) , 235-244.
    24. Imran Sajid, Khaled A. Shaaban, Shahida Hasnain. Antitumour compounds from a saline soil isolate, Streptomyces griseoincarnatus CTF15. Natural Product Research 2011, 25 (5) , 549-559.
    25. Vineeta Singh, Mahvish Khan, Saif Khan, C. K. M. Tripathi. Optimization of actinomycin V production by Streptomyces triostinicus using artificial neural network and genetic algorithm. Applied Microbiology and Biotechnology 2009, 82 (2) , 379-385.
    26. Jens Bitzer, Martin Streibel, Hans-Jörg Langer, Stephanie Grond. First Y-type actinomycins from Streptomyces with divergent structure-activity relationships for antibacterial and cytotoxic properties. Org. Biomol. Chem. 2009, 7 (3) , 444-450.
    27. Anthony Mauger, Helmut Lackner. The Actinomycins. 2005
    28. Cormac D. Murphy, Christoph Schaffrath, David O’Hagan. Fluorinated natural products: the biosynthesis of fluoroacetate and 4-fluorothreonine in Streptomyces cattleya. Chemosphere 2003, 52 (2) , 455-461.
    29. Nuria Bayó, Jose C. Jiménez, Luis Rivas, Ernesto Nicolás, Fernando Albericio. Solid‐Phase Synthesis of the Cyclic Lipononadepsipeptide [ N ‐Mst(Ser1), D ‐Ser4, L ‐Thr6, L ‐Asp8, L ‐Thr9]Syringotoxin. Chemistry – A European Journal 2003, 9 (5) , 1096-1103.
    30. T. Řezanka, J. Spížek. Halogen-Containing Antibiotics From Streptomycetes. 2003, 309-353.
    31. Cormac D. Murphy, David O'Hagan, Christoph Schaffrath. Identification of a PLP-Dependent Threonine Transaldolase: A Novel Enzyme Involved in 4-Fluorothreonine Biosynthesis inStreptomyces cattleya. Angewandte Chemie 2001, 113 (23) , 4611-4613.<4611::AID-ANGE4611>3.0.CO;2-U

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect