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記事

24 引用 (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.

元の言語英語
ページ(範囲)5928-5939
ページ数12
ジャーナルJournal of Physical Chemistry B
114
発行部数17
DOI
出版物ステータス出版済み - 5 6 2010

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Intramolecular Transferases
methylaspartate mutase
tyrosine
Methylmalonyl-CoA Mutase
Catalysis
catalysis
Tyrosine
Protons
enzymes
electron transfer
Enzymes
glutamates
Electrons
protons
cleavage
Chemical activation
activation
Electronic states
structural analysis
Discrete Fourier transforms

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

これを引用

Theoretical analysis of the diradical nature of adenosylcobalamin cofactor-tyrosine complex in B12-dependent mutases : Inspiring PCET-driven enzymatic catalysis. / Kozlowski, Pawel M.; Kamachi, Takashi; Kumar, Manoj; Nakayama, Tomonori; Yoshizawa, Kazunari.

:: Journal of Physical Chemistry B, 巻 114, 番号 17, 06.05.2010, p. 5928-5939.

研究成果: ジャーナルへの寄稿記事

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abstract = "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.",
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