QM/MM study of catalytic methyl transfer by the N5-glutamine SAM-dependent methyltransferase and its inhibition by the nitrogen analogue of coenzyme
✍ Scribed by Ruibo Wu; Zexing Cao
- Book ID
- 102876894
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 603 KB
- Volume
- 29
- Category
- Article
- ISSN
- 0192-8651
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✦ Synopsis
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. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2008