Cyclomarins A-C are potent anti-inflammatory cyclic peptides originally encountered in the estuarine streptomycete, strain CNB-982.  Subsequently, cyclomarin A, C, and D, along with the truncated diketopiperazine cyclomarazines A-B were isolated from the marine obligate actinobacterium Salinispora arenicola CNS-205.  The cyclomarins are composed of seven amino acid residues, two of which are of biosynthetic interest, 2-amino-3,5-dimethylhex-4-enoic acid (ADH), which has never been reported as a constituent of any peptide, and N-(1,1-dimethyl-2,3-epoxypropyl)-β-hydroxytryptophan.  The N-prenylated tryptophan residue is present in both the cyclomarins and cyclomarazines, and has been reported in only one other natural product, the ilamycins from Streptomyces islandicus.

Because of the unique structural features of these two residues, interrogation of the biosynthetic machinery behind cyclomarin and cyclomarazine synthesis was initiated.  We were able to determine the basic steps of cyclomarin and cyclomarazine production, along with insights into how the two unique amino acids are synthesized.  Functional characterization of the prenyltransferase, CymD, revealed its ability to prenylate tryptophan in the absence of any peptidyl carrier proteins utilizing dimethylallyl pyrophosphate as a substrate.  Here we report a comprehensive investigation of cyclomarin biosynthesis at the chemistry-biology interface involving the description of new structural analogs, precursor incorporation studies, gene cluster sequence analysis, and in vivo functional analysis.

Reference:  Schultz, A.;  Oh, D.-C.; Carney, J.R.; Williamson, R. T.; Udwary, D. W; Jensen, P. R.; Gould, S .J. Fenical, W. and Moore, B.S.  J. Am. Chem. Soc. 2008, 130, 4507 -4516