Reductive elimination pathway for homocysteine to methionine conversion in cobalamin-dependent methionine synthase

Pawel M. Kozlowski, Takashi Kamachi, Manoj Kumar, Kazunari Yoshizawa

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Density functional theory has been applied to investigate the methyl transfer from methylcobalamin (MeCbl) cofactor to homocysteine (Hcy) as catalyzed by methionine synthase (MetH). Specifically, the SN2 and the reductive elimination pathways have been probed as the possible mechanistic pathways for the methyl transfer reaction. The calculations indicate that the activation barrier for the reductive elimination reaction (24.4 kcal mol-1) is almost four times higher than that for the SN2 reaction (7.3 kcal mol-1). This high energy demand of the reductive elimination pathway is rooted in the structural distortion of the corrin ring that is induced en route to the formation of the triangular transition state. Furthermore, the reductive elimination reaction demands the syn accommodation of the methyl group and the substrate over the upper face of the corrin ring, which also accounts for the high energy demand of the reaction. Consequently, the reductive elimination pathway for MetH-catalyzed methyl transfer fromMeCbl to Hcy cannot be considered as one of the possible mechanistic routes.

Original languageEnglish
Pages (from-to)611-619
Number of pages9
JournalJournal of Biological Inorganic Chemistry
Volume17
Issue number4
DOIs
Publication statusPublished - Apr 1 2012

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5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
Homocysteine
Vitamin B 12
Methionine
Density functional theory
Chemical activation
Substrates
corrin
mecobalamin

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Inorganic Chemistry

Cite this

Reductive elimination pathway for homocysteine to methionine conversion in cobalamin-dependent methionine synthase. / Kozlowski, Pawel M.; Kamachi, Takashi; Kumar, Manoj; Yoshizawa, Kazunari.

In: Journal of Biological Inorganic Chemistry, Vol. 17, No. 4, 01.04.2012, p. 611-619.

Research output: Contribution to journalArticle

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AB - Density functional theory has been applied to investigate the methyl transfer from methylcobalamin (MeCbl) cofactor to homocysteine (Hcy) as catalyzed by methionine synthase (MetH). Specifically, the SN2 and the reductive elimination pathways have been probed as the possible mechanistic pathways for the methyl transfer reaction. The calculations indicate that the activation barrier for the reductive elimination reaction (24.4 kcal mol-1) is almost four times higher than that for the SN2 reaction (7.3 kcal mol-1). This high energy demand of the reductive elimination pathway is rooted in the structural distortion of the corrin ring that is induced en route to the formation of the triangular transition state. Furthermore, the reductive elimination reaction demands the syn accommodation of the methyl group and the substrate over the upper face of the corrin ring, which also accounts for the high energy demand of the reaction. Consequently, the reductive elimination pathway for MetH-catalyzed methyl transfer fromMeCbl to Hcy cannot be considered as one of the possible mechanistic routes.

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