Molecular and Biochemical Studies of Chondramide Formation-Highly Cytotoxic Natural Products from Chondromyces crocatus Cm c5

Shwan Rachid, Daniel Krug, Brigitte Kunze, Irene Kochems, Maren Scharfe, Mark Zabriskie, Helmut Blöcker, Rolf Müller

Research output: Contribution to journalArticle

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Abstract

The jaspamide/chondramide family of depsipeptides are mixed PKS/NRPS natural products isolated from marine sponges and a terrestrial myxobacterium that potently affect the function of the actin cytoskeleton. As a first step to improve production in heterologous host cells and permit genetic approaches to novel analogs, we have cloned and characterized the chondramide biosynthetic genes from the myxobacterium Chondromyces crocatus Cm c5. In addition to the expected PKS and NRPS genes, the cluster encodes a rare tyrosine aminomutase for β-tyrosine formation and a previously unknown tryptophan-2-halogenase. Conditions for gene transfer into C. crocatus Cm c5 were developed, and inactivation of several genes corroborated their proposed function and served to define the boundaries of the cluster. Biochemical characterization of the final NRPS adenylation domain confirmed the direct activation of β-tyrosine, and fluorinated chondramides were produced through precursor-directed biosynthesis.

Original languageEnglish (US)
Pages (from-to)667-681
Number of pages15
JournalChemistry and Biology
Volume13
Issue number6
DOIs
Publication statusPublished - Jun 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Organic Chemistry

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