title: QM/MM study of catalytic methyl transfer by the N5-glutamine SAM-dependent methyltransferase and its inhibition by the nitrogen analogue of coenzyme.
abstract: The combined density functional quantum mechanical/molecular mechanical (QM/MM) approach has been used to investigate methyl-transfer reactions catalyzed by the N(5)-glutamine S-adenosyl-L-methionine (SAM)-dependent methyltransferase (HemK) and the coenzyme-modified HemK with the replacement of SAM by a nitrogen analogue. Calculations reveal that the catalytic methyl transfer by HemK is an energy-favored process with an activation barrier of 15.7 kcal/mol and an exothermicity of 12.0 kcal/mol, while the coenzyme-modified HemK is unable to catalyze the methyl transfer because of a substantial barrier of 20.6 kcal/mol and instability of the product intermediate. The results lend support to the experimental proposal that the nitrogen analogue of the SAM coenzyme should be a practicable inhibitor for the catalytic methyl transfer by HemK. Comparative QM/MM calculations show that the protein environment, especially the residues Asn197 and Pro198 in the active site, plays a pivotal role in stabilizing the transition state and regulating the positioning of reactive groups.
authors.affiliation: Department of Chemistry and State Key Laboratory of Physical Chemistry of Solid Surfaces, Xiamen University, Xiamen 361005, China.
authors.forename: Ruibo
authors.initials: R
authors.lastname: Wu
authors.forename: Zexing
authors.initials: Z
authors.lastname: Cao
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D003067:Coenzymes / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D005973:Glutamine / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D003067:Coenzymes; D005973:Glutamine; D011496:Protein Methyltransferases; D009584:Nitrogen