Deconstruction of iterative multidomain polyketide synthase function

Jason M. Crawford, Paul M. Thomas, Jonathan R. Scheerer, Anna L. Vagstad, Neil L. Kelleher, Craig A. Townsend

Research output: Contribution to journalArticlepeer-review

153 Scopus citations

Abstract

PksA, which initiates biosynthesis of the environmental carcinogen aflatoxin B1, is one of the multidomain iterative polyketide synthases (IPKSs), a large, poorly understood family of biosynthetic enzymes. We found that dissection of PksA and its reconstitution from selected sets of domains allows the accumulation and characterization of advanced octaketide intermediates bound to the enzyme, permitting the reactions controlled by individual catalytic domains to be identified. A product template (PT) domain unites with the ketosynthase and thioesterase in this IPKS system to assemble precisely seven malonyl-derived building blocks to a hexanoyl starter unit and mediate a specific cyclization cascade. Because the PT domain is common among nonreducing IPKSs, these mechanistic features should prove to be general for IPKS-catalyzed production of aromatic polyketides.

Original languageEnglish (US)
Pages (from-to)243-246
Number of pages4
JournalScience
Volume320
Issue number5873
DOIs
StatePublished - Apr 11 2008

ASJC Scopus subject areas

  • General

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