Convergence of isoprene and polyketide biosynthetic machinery: Isoprenyl-S-carrier proteins in the pksX pathway of Bacillus subtilis

Christopher T. Calderone, Walter E. Kowtoniuk, Neil L. Kelleher*, Christopher T. Walsh, Pieter C. Dorrestein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

124 Scopus citations

Abstract

The pksX gene cluster from Bacillus subtilis is predicted to encode the biosynthesis of an as yet uncharacterized hybrid nonribosomal peptide/polyketide secondary metabolite. We used a combination of biochemical and mass spectrometric techniques to assign functional roles to the proteins AcpK, PksC, PksL, PksF, PksG, PksH, and PksI, and we conclude that they act to incorporate an acetate-derived β-methyl branch on an acetoacetyl-S-carrier protein and ultimately generate a Δ2-isoprenyl-S-carrier protein. This work highlights the power of mass spectrometry to elucidate the functions of orphan biosynthetic enzymes, and it details a mechanism by which single-carbon β-branches can be inserted into polyketide-like structures. This pathway represents a noncanonical route to the construction of prenyl units and serves as a prototype for the intersection of isoprenoid and polyketide biosynthetic manifolds in other natural product biosynthetic pathways.

Original languageEnglish (US)
Pages (from-to)8977-8982
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number24
DOIs
StatePublished - Jun 13 2006

Keywords

  • Hybrid nonribosomal peptide/polyketide
  • Mass spectrometry
  • Orphan gene cluster
  • Polyketide methylation

ASJC Scopus subject areas

  • General

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