Theoretical analysis of the diradical nature of adenosylcobalamin cofactor-tyrosine complex in B12-dependent mutases: Inspiring PCET-driven enzymatic catalysis

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

研究成果: ジャーナルへの寄稿学術誌査読

26 被引用数 (Scopus)

抄録

Detailed theoretical and X-ray based structural analysis has been carried out in order to unmask the role of the tyrosine residue (Y) in the activation of the Co-C bond in AdoCbl-dependent mutases. In particular, methylmalonyl-CoA mutase (MCM) and glutamate mutase (GLM) enzymes have been studied; in the case of MCM, the significance of the Y89 residue has been analyzed extensively. Three different theoretical platforms encompassing the DFT, CASSCF/QDPT2, and QM/MM frameworks have been employed to elucidate the energetics of the AdoCbl-Y - complex while taking into account a varied degree of structural complexity. The diradical state, [AdoCbl]•--Y, has been found to be the lowest electronic state of the AdoCbl-Y- complex, providing strong evidence that electron transfer from the Y89 residue to the cofactor is feasible. Crystallographic analysis of the active sites of MCM and GLM enzymes reveals that substrate binding can play a critical role in displacing the hydroxyl proton of the Y residue (Y89 in the case of MCM enzyme and Y181 in the case of GLM enzyme) that will facilitate the electron transfer (ET), hence making the activation process a case of proton-coupled electron transfer (PCET). PCET-inspired enzymatic catalysis implies that the cleavage of the Co-C bond takes place via one-electron reduced form of the AdoCbl cofactor (i.e., [AdoCbl]•-), rather than its neutral analogue, thus providing an efficient mode of cleavage that can help in understanding the origin of the catalytic effect in such enzymes.

本文言語英語
ページ(範囲)5928-5939
ページ数12
ジャーナルJournal of Physical Chemistry B
114
17
DOI
出版ステータス出版済み - 5月 6 2010

!!!All Science Journal Classification (ASJC) codes

  • 物理化学および理論化学
  • 表面、皮膜および薄膜
  • 材料化学

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