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Publication Abstract from PubMed

Modular type I polyketide synthases (PKSs) produce some of the most chemically complex metabolites in nature through a series of multi-enzyme modules. Each module contains a variety of catalytic domains to selectively tailor the growing molecule. PKS O-methyltransferases ( O-MTs) are predicted to methylate beta-hydroxyl or beta-keto groups but their activity and structure have not been reported. We determined the domain boundaries and characterized the catalytic activity and structure of the StiD and StiE O-MTs, which methylate opposite beta-hydroxyl stereocenters in the myxobacterial stigmatellin biosynthetic pathway. Substrate stereospecificity was demonstrated for the StiD O-MT. Key catalytic residues were identified in the crystal structures and investigated in StiE O-MT via site-directed mutagenesis and further validated with the cyanobacterial CurL O-MT from the curacin biosynthetic pathway. Initial structural and biochemical analysis of PKS O-MTs supplies a new chemoenzymatic tool, with the unique ability to selectively modify hydroxyl groups during polyketide biosynthesis.

Structural Basis of Polyketide Synthase O-Methylation.,Skiba MA, Bivins MM, Schultz JR, Bernard SM, Fiers WD, Dan Q, Kulkarni S, Wipf P, Gerwick WH, Sherman DH, Aldrich CC, Smith JL ACS Chem Biol. 2018 Nov 29. doi: 10.1021/acschembio.8b00687. PMID:30489068^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.