Structural basis of polyketide synthase o-methylation

TitleStructural basis of polyketide synthase o-methylation
Publication TypeJournal Article
Year of Publication2018
AuthorsSkiba M.A, Bivins M.M, Schultz J.R, Bernard S.M, Fiers W.D, Dan Q.Y, Kulkarni S., Wipf P., Gerwick WH, Sherman D.H, Aldrich C.C, Smith J.L
JournalAcs Chemical Biology
Volume13
Pagination3221-3228
Date Published2018/12
Type of ArticleArticle
ISBN Number1554-8929
Accession NumberWOS:000454568000002
KeywordsBiochemistry & Molecular Biology; biosynthetic gene-cluster; carrier; dehydratase domain; domains; ketoreductase; mechanism; methyltransferase; myxobacteria; natural-product; organization; stereospecificity
Abstract

Modular type I polyketide synthases (PKSs) produce some of the most chemically complex metabolites in nature through a series of multienzyme 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 .

DOI10.1021/acschembio.8b00687
Short TitleACS Chem. Biol.
Student Publication: 
No
Research Topics: 
sharknado