Polyketide chain skipping mechanism in the biosynthesis of the hybrid nonribosomal peptide-polyketide antitumor antibiotic leinamycin in Streptomyces atroolivaceus S-140

Gong Li Tang, Yi Qiang Cheng, Ben Shen

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

A fundamental feature of modular polyketide synthases (PKSs) is the highly predictable relationship between the domain order and the chemical functional groups of resultant polyketide products. Sequence analysis and biochemical characterization of the leinamycin (LNM) biosynthetic gene cluster from Streptomyces atroolivaceus S-140 has revealed a gene, lnmJ, that encodes five PKS modules but with six acyl carrier protein (ACP) domains. The LnmJ PKS module 6 contains two ACP domains, ACP6-1 and ACP6-2, separated by a C-methyltransferase domain. Site-directed mutagenesis experiments were carried out with each of these ACPs to test alternative mechanisms proposed for their role in polyketide chain elongation. The in vivo results revealed a new type of polyketide chain "skipping" mechanism, in which either ACP is sufficient for LNM biosynthesis. Biochemical characterization in vitro showed that both ACPs can be loaded with a malonate extender unit by the LnmG acyl transferase; however, ACP6-2 appears to be preferred because the loading efficiency is about 5-fold that of ACP6-1. The results are consistent with ACP6-2 being used for the initial chain elongation step wth ACP6-1 being involved in the ensuing C-methylation process. These findings provide new insights into the polyketide chain skipping mechanism for modular PKSs.

Original languageEnglish
Pages (from-to)387-393
Number of pages7
JournalJournal of Natural Products
Volume69
Issue number3
DOIs
StatePublished - Mar 2006

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