Structural highlights
FunctionPublication Abstract from PubMedInstallation of methyl groups can significantly improve the binding of small-molecule drugs to protein targets; however, site-selective methylation often presents a significant synthetic challenge. Metal- and S-adenosyl-methionine (SAM)-dependent methyltransferases (MTs) in natural-product biosynthetic pathways are powerful enzymatic tools for selective or chemically challenging C-methylation reactions. Each of these MTs selectively catalyzes one or two methyl transfer reactions. Crystal structures and biochemical assays of the Mn(2+)-dependent monomethyltransferase from the saxitoxin biosynthetic pathway (SxtA MT) revealed the structural basis for control of methylation extent. The SxtA monomethyltransferase was converted to a dimethyltransferase by modification of the metal binding site, addition of an active site base, and an amino acid substitution to provide space in the substrate pocket for two methyl substituents. A reciprocal change converted a related dimethyltransferase into a monomethyltransferase, supporting our hypothesis that steric hindrance can prevent a second methylation event. A novel understanding of MTs will accelerate the development of MT-based catalysts and MT engineering for use in small-molecule synthesis. Structural Basis for Control of Methylation Extent in Polyketide Synthase Metal-Dependent C-Methyltransferases.,Lao Y, Skiba MA, Chun SW, Narayan ARH, Smith JL ACS Chem Biol. 2022 Aug 19;17(8):2088-2098. doi: 10.1021/acschembio.2c00085. Epub, 2022 May 20. PMID:35594521[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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