Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization

Jason M. Crawford, Tyler P. Korman, Jason W. Labonte, Anna L. Vagstad, Eric A. Hill, Oliver Kamari-Bidkorpeh, Shiou-Chuan Tsai () and Craig A. Townsend ()
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Jason M. Crawford: Department of Chemistry,
Tyler P. Korman: Department of Molecular Biology and Biochemistry,
Jason W. Labonte: Department of Chemistry,
Anna L. Vagstad: Department of Chemistry,
Eric A. Hill: Department of Chemistry,
Oliver Kamari-Bidkorpeh: Department of Chemistry,
Shiou-Chuan Tsai: Department of Molecular Biology and Biochemistry,
Craig A. Townsend: Department of Chemistry,

Nature, 2009, vol. 461, issue 7267, 1139-1143

Abstract: Fungal toxin biosynthesis Polyketides are a class of natural products with diverse structures and biological activities. Here, Jason Crawford and colleagues report the X-ray crystal structure of a domain of the iterative polyketide synthase that is responsible for generating the potent hepatocarcinogen aflatoxin B1. This domain — called the product template (PT) domain – catalyses the stepwise intramolecular aldol cyclizations and their dehydrations to yield a bicyclic ACP–thioester intermediate. Co-crystal structures of this protein with palmitate or a bicyclic substrate mimic show that the PT domain is able to bind both linear and bicyclic compounds. The authors identify a large cyclization chamber and propose how the PT domain controls the specificity of the biosynthetic reactions that generate the intermediate that is eventually converted into aflatoxin B1.

Date: 2009
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DOI: 10.1038/nature08475

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