QM/MM study of catalytic methyl transfer by the N5-Glutamine SAM-dependent methyltransferase and its inhibition by the nitrogen analogue of coenzyme

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. (C) 2007 Wiley Periodicals, Inc.