Dissecting non-ribosomal and polyketide biosynthetic machineries using electrospray ionization Fourier-Transform mass spectrometry

Pieter C. Dorrestein*, Neil L. Kelleher

*Corresponding author for this work

Research output: Contribution to journalReview article

47 Scopus citations

Abstract

Many virulence factors and bioactive compounds with antifungal, antimicrobial, and antitumor properties are produced via the non-ribosomal peptide synthetase (NRPS) or polyketide synthase (PKS) paradigm. During the biosynthesis of these natural products, substrates, intermediates and side products are covalently tethered to the NRPS or PKS catalyst, introducing mass changes, making these biosynthetic systems ideal candidates for interrogation by large molecule mass spectrometry. This review serves as an introduction into the application of electrospray ionization Fourier-Transform mass spectrometry (ESI-FTMS) to investigate NRPS and PKS systems. ESI-FTMS can be used to understand substrate tolerance, timing of covalent linkages, timing of tailoring reactions and the transfer of substrates and biosynthetic intermediates from domain to domain. Therefore we not only highlight key mechanistic insights for thiotemplate systems as found on the enterobactin, yersiniabactin, epothilone, clorobiocin, coumermycin, pyoluteorin, gramicidin, mycosubtilin, C-1027, 6-deoxyerythronolide B and FK520 biosynthetic pathways, but we also explain the approaches taken to identify active sites from complex digests and compare the FTMS based assay to traditional assays and other mass spectrometric techniques. Although mass spectrometry was introduced over two decades ago to investigate NRPS and PKS biosynthetic systems, this is the first review devoted to this methodology.

Original languageEnglish (US)
Pages (from-to)893-918
Number of pages26
JournalNatural product reports
Volume23
Issue number6
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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