Hydroxymalonyl-acyl carrier protein (ACP) and aminomalonyl-ACP are two additional type I polyketide synthase extender units

Yolande A. Chan, Michael T. Boyne, Angela M. Podevels, Amy K. Klimowicz, Jo Handelsman, Neil L. Kelleher, Michael G. Thomas*

*Corresponding author for this work

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

Combinatorial biosynthesis of type I polyketide syntheses is a promising approach for the generation of new structural derivatives of polyketide-containing natural products. A target of this approach has been to change the extender units incorporated into a polyketide backbone to alter the structure and activity of the natural product. One limitation to these efforts is that only four extender units were known: malonyl-CoA, methylmalonyl-CoA, ethylmalonyl-CoA, and methoxymalonyl-acyl carrier protein (ACP). The chemical attributes of these extender units are quite similar, with the exception of the potential hydrogen bonding interactions by the oxygen of the methoxy moiety. Furthermore, the incorporated extender units are not easily modified by using simple chemical approaches when combinatorial biosynthesis is coupled to semisynthetic chemistry. We recently proposed the existence of two additional extender units, hydroxymalonyl-ACP and aminomalonyl-ACP, involved in the biosynthesis of zwittermicin A. These extender units offer unique possibilities for combinatorial biosynthesis and semisynthetic chemistry because of the introduction of free hydroxyl and amino moieties into a polyketide structure. Here, we present the biochemical and mass spectral evidence for the formation of these extender units. This evidence shows the formation of ACP-linked extender units for polyketide synthesis. Interestingly, aminomalonyl-ACP formation involves enzymology typically found in nonribosomal peptide synthesis.

Original languageEnglish (US)
Pages (from-to)14349-14354
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number39
DOIs
StatePublished - Sep 26 2006

Keywords

  • Antibiotics
  • Combinatorial biosynthesis

ASJC Scopus subject areas

  • General

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