title: Convergent Mechanistic Features between the Structurally Diverse N- and O-Methyltransferases: Glycine N-Methyltransferase and Catechol O-Methyltransferase.
abstract: Although an enormous and still growing number of biologically diverse methyltransferases have been reported and identified, a comprehensive understanding of the enzymatic methyl transfer mechanism is still lacking. Glycine N-methyltransferase (GNMT), a member of the family that acts on small metabolites as the substrate, catalyzes methyl transfer from S-adenosyl-l-methionine (AdoMet) to glycine to form S-adenosyl-l-homocysteine and sarcosine. We report primary carbon ((12)C/(14)C) and secondary ((1)H3/(3)H3) kinetic isotope effects at the transferred methyl group, together with (1)H3/(3)H3 binding isotope effects for wild-type GNMT and a series of Tyr21 mutants. The data implicate a compaction effect in the methyl transfer step that is conferred by the protein structure. Furthermore, a remarkable similarity of properties is observed between GNMT and catechol O-methyltransferase, despite significant differences between these enzymes with regard to their active site structures and catalyzed reactions. We attribute these results to a catalytically relevant reduction in the methyl donor-acceptor distance that is dependent on a tyrosine side chain positioned behind the methyl-bearing sulfur of AdoMet.
authors.affiliation: Department of Chemistry, ‡Department of Molecular and Cell Biology, and §California Institute for Quantitative Biosciences, University of California , Berkeley, California 94720, United States.
authors.forename: Jianyu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, ‡Department of Molecular and Cell Biology, and §California Institute for Quantitative Biosciences, University of California , Berkeley, California 94720, United States.
authors.forename: Judith P
authors.initials: JP
authors.lastname: Klinman
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002394:Catechol O-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050938:Glycine N-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D008958:Models, Molecular; D009154:Mutation; D051381:Rats
chemical_list: D050938:Glycine N-Methyltransferase; D002394:Catechol O-Methyltransferase