Unusual Chemistry in the Biosynthesis of the Antibiotic Chondrochlorens

Abstract

The antibiotic chondrochlorens A and B from the myxobacterium Chondromyces crocatus Cm c5 incorporate several unusual structural features, notable among them a shared chloro-hydroxy-styryl functionality and the ethoxy group of chondrochloren B. Our analysis of the chondrochloren gene cluster by targeted gene inactivation coupled with assays in vitro has shed significant light on the biosynthesis of these metabolites. Chlorination of tyrosine occurs early in the pathway, likely on a peptidyl carrier protein-bound intermediate, whereas decarboxylation to the styryl moiety appears to be accomplished by an unprecedented oxidative decarboxylase. We also show that the chondrochloren B ethoxy group arises from initial incorporation by the polyketide synthase of hydroxy malonate as an extender unit, methylation in cis by an O-methyltransferase, followed by a second methylation. This report therefore constitutes a direct demonstration of the involvement of a radical S-adenosylmethionine methylase in bacterial secondary metabolism.