Biosynthetic pathway and gene cluster analysis of curacin A, an antitubulin natural product from the tropical marine cyanobacterium Lyngbya majuscula

Curacin A (1) is a potent cancer cell toxin obtained from strains of the tropical marine cyanobacterium Lyngbya majuscula found in Curaçao. Its structure is unique in that it contains the sequential positioning of a thiazoline and cyclopropyl ring, and it exerts its potent cell toxicity through inte...

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Bibliographic Details
Published in:	Journal of natural products (Washington, D.C.) Vol. 67; no. 8; pp. 1356 - 1367
Main Authors:	Chang, Z, Sitachitta, N, Rossi, J.V, Roberts, M.A, Flatt, P.M, Jia, J, Sherman, D.H, Gerwick, W.H
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-08-2004 Glendale, AZ American Society of Pharmacognosy
Subjects:	Amino Acid Sequence Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents Antineoplastic agents Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Applied microbiology Biological and medical sciences Chemotherapic agents Cyanobacteria - chemistry Cyanobacteria - genetics Cyanobacteria - metabolism Cyanophyta Cyclopropanes - metabolism Cyclopropanes - pharmacology Fundamental and applied biological sciences. Psychology General aspects Lyngbya majuscula Marine Marine Toxins - metabolism Marine Toxins - pharmacology Medical sciences Microbiology Mitosis - drug effects Molecular Sequence Data Molecular Structure Nuclear Magnetic Resonance, Biomolecular Pharmacology. Drug treatments Sequence Alignment Thiazoles - metabolism Thiazoles - pharmacology Tubulin Modulators ASW, Caribbean Sea, Netherlands Antilles, Curacao Cluster analysis Antineoplastic agent Gene cluster Cyclopropane derivatives Enzyme Aliphatic compound Thiazole derivatives Biosynthesis Marine environment Gene Microbial origin Polyenic compound Ligases Cyanobacteria Bacteria Isolation Antimitotic
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Summary:	Curacin A (1) is a potent cancer cell toxin obtained from strains of the tropical marine cyanobacterium Lyngbya majuscula found in Curaçao. Its structure is unique in that it contains the sequential positioning of a thiazoline and cyclopropyl ring, and it exerts its potent cell toxicity through interaction with the colchicine drug binding site on microtubules. A series of stable isotope-labeled precursors were fed to cultures of curacin A-producing strains and, following NMR analysis, allowed determination of the metabolic origin of all atoms in the natural product (one cysteine, 10 acetate units, two S-adenosyl methionine-derived methyl groups) as well as several unique mechanistic insights. Moreover, these incorporation experiments facilitated an effective gene cloning strategy that allowed identification and sequencing of the approximately 64 kb putative curacin A gene cluster. The metabolic system is comprised of a nonribosomal peptide synthetase (NRPS) and multiple polyketide synthases (PKSs) and shows a very high level of collinearity between genes in the cluster and the predicted biochemical steps required for curacin biosynthesis. Unique features of the cluster include (1) all but one of the PKSs are monomodular multifunctional proteins, (2) a unique gene cassette that contains an HMG-CoA synthase likely responsible for formation of the cyclopropyl ring, and (3) a terminating motif that is predicted to function in both product release and terminal dehydrative decarboxylation.
Bibliography:	ark:/67375/TPS-60RPSZRS-W Dedicated to the late Dr. D. John Faulkner (Scripps) and the late Dr. Paul J. Scheuer (Hawaii) for their pioneering work on bioactive marine natural products. istex:EFD50C3A543FDE0574FE3C3D08A8C30C9272B673 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0163-3864 1520-6025
DOI:	10.1021/np0499261