Detailed theoretical and X-raybased structural analysis has been carried out in order to unmask the role oftyrosine residue (Y) in the activation of the Co-C bond in AdoCbl-dependentmutases. In particular, methylmalonyl-CoA mutase (MCM) and glutamatemutase (GLM) enzymes havebeen studied while in the case of MCM, the significance of the Y89 residue hasbeen analyzed extensively. Three different theoretical platforms encompassingDFT, CASSCF/QDPT2,and QM/MM framework have been employed to elucidate the energetic of the AdoCbl-Y- complex while taking into account a varied degree ofstructural complexity. The diradical state, [AdoCbl]�--Y�, has been found to be the lowest electronic state of theAdoCbl-Y- complex providing strong evidencethat the electron transfer from Y89 residue to the cofactor is feasible.Crystallographic analysis of the active sites of MCM and GLM enzymes revealsthat substrate binding can play a critical role in displacing the hydroxylproton of Y residue (Y89 in case of MCM enzyme and Y181 in case of GLM enzyme)that will facilitate the electron transfer (ET), hence making the activationprocess a case of proton-coupled electron transfer (PCET). PCET-inspiredenzymatic catalysis implies that the cleavage of the Co-C bond takes place inone-electron reduced form of AdoCbl cofactor (i.e. [AdoCbl]�-), rather than neutral analogue,thus providing an efficient mode of cleavage that can help in understanding theorigin of catalytic effect in such enzymes.

Theoretical analysis of diradical nature of Adenosylcobalamin cofactor –tyrosine complex in
B<sub>12</sub>-dependent mutases: Inspiring PCET-driven enzymatic catalysis

241st National Meeting (2011)

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

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