QM/MM study of catalytic methyl transfer by the N5-glutamine SAM-dependent methyltransferase and its inhibition by the nitrogen analogue of coenzyme
(c) 2007 Wiley Periodicals, Inc.
| Publié dans: | Journal of computational chemistry. - 1984. - 29(2008), 3 vom: 15. Feb., Seite 350-7 |
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| Format: | Article en ligne |
| Langue: | English |
| Publié: |
2008
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| Accès à la collection: | Journal of computational chemistry |
| Sujets: | Journal Article Research Support, Non-U.S. Gov't Coenzymes Glutamine 0RH81L854J Protein Methyltransferases EC 2.1.1.- Nitrogen N762921K75 |
| Résumé: | (c) 2007 Wiley Periodicals, Inc. 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 |
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| Description: | Date Completed 18.04.2008 Date Revised 21.11.2013 published: Print Citation Status MEDLINE |
| ISSN: | 1096-987X |