Mechanistic Insights for Formation of an Organometallic Co鈥揅 Bond in the Methyl Transfer Reaction Catalyzed by Methionine Synthase

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• 作者：Neeraj Kumar ; Pawel M. Kozlowski
• 刊名：Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：December 19, 2013
• 年：2013
• 卷：117
• 期：50
• 页码：16044-16057
• 全文大小：555K
• 年卷期：v.117,no.50(December 19, 2013)
• ISSN：1520-5207

文摘

Methionine synthase (MetH) catalyzes the transfer of a methyl group from methyltetrahydrofolate (CH₃鈥揌₄Folate) to the cob(I)alamin intermediate to form an organometallic Co鈥揅 bond, a reaction similar to that of CH₃鈥揌₄Folate:corrinoid/iron鈥搒ulfur protein (CFeSP) methyltransferase (MeTr). How precisely it is formed remains elusive because the displacement of a methyl group from the tertiary amine is not a facile reaction. To understand the electronic structure and mechanistic details of the MetH鈥揷ob(I)alamin:CH₃鈥揌₄Folate reaction complex, we applied quantum mechanics/molecular mechanics (QM/MM) computations. The hybrid QM/MM calculations reveal the traditionally assumed S_N2 mechanism for formation the CH₃鈥揷ob(III)alamin resting state where the activation energy barrier for the S_N2 reaction was found to be 8鈥? kcal/mol, which is comparable with respect to the determined experimental rate constant. However, the possibility of an electron transfer (ET) based radical mechanism consistent with the close-lying diradical states observed from triplet and open-shell singlet states has also been suggested as an alternative, where first an electron transfer from His-on cob(I)alamin to the pterin ring of the protonated CH₃鈥揌₄Folate takes place, forming the Co^II(d⁷)鈥損terin radical (蟺*)¹ diradical state, followed by a methyl radical transfer. Although the predicted energy barrier for the ET-mediated radical reaction is comparable to that of the S_N2 pathway, the major advantage of ET is that a methyl radical can be transferred at a longer distance, which does not require the close proximity of two binding modules of MetH as does the S_N2 type. In addition, based on the energy barrier of the transition state (TS) in both the protonated (8鈥? kcal/mol) and the unprotonated N5 (39 kcal/mol) species of the CH₃鈥揌₄Folate, it can be inferred that the protonation event must takes place either prior to or during the methyl transfer reaction in a ternary complex. The results of the present study including mechanistic insights can have implications to a broad class of corrinoid鈥搈ethyltransferases, which utilize a CH₃鈥揌₄Folate substrate or its related analogues as methyl donor.