Non-linear enzymatic logic in natural product modular mega-synthases and -synthetases

Stuart W. Haynes, Gregory L. Challis

Research output: Contribution to journalReview ArticleResearchpeer-review

31 Citations (Scopus)


Modular polyketide synthases and nonribosomal peptide synthetases are giant multienzymes that catalyze the assembly of a wide variety of bioactive natural products including several important clinical drugs. In simple mechanical terms, these systems function as molecular assembly lines, where each domain in the multienzyme performs its task once during the assembly process. However, several polyketide synthase and nonribosomal peptide synthetase systems have been discovered with architectures that suggest a deviation from this assembly line mechanistic logic. This article discusses progress toward understanding the mechanistic logic underlying suchnon-linear systems, identifies areas where further mechanistic insight into these systems is required and reflects on the likely consequences of non-linear enzymatic logic for attempts to genetically engineer modular polyketide synthases and nonribosomal peptide synthetases to produce analogs of bioactive natural products.

Original languageEnglish
Pages (from-to)203-218
Number of pages16
JournalCurrent Opinion in Drug Discovery & Development
Issue number2
Publication statusPublished - 1 Mar 2007
Externally publishedYes


  • Biosynthesis
  • Co-linearity
  • Mechanistic enzymology
  • Modular synthase
  • Modular synthetase
  • Non-ribosomal peptide
  • Nonlinearity
  • Polyketide

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