Computational insights into the mechanism of radical generation in B12-dependent methylmalonyl-CoA mutase.
ONIOM calculations have provided novel insights into the mechanism of homolytic Co-C5' bond cleavage in the 5'-deoxyadenosylcobalamin cofactor catalyzed by methylmalonyl-CoA mutase. We have shown that it is a stepwise process in which conformational changes in the 5'-deoxyadenosine moiety precede the actual homolysis step. In the transition state structure for homolysis, the Co-C5' bond elongates by approximately 0.5 Angstroms from the value found in the substrate-bound reactant complex. The overall barrier to homolysis is approximately 10 kcal/mol, and the radical products are approximately 2.5 kcal/mol less stable than the initial ternary complex of enzyme, substrate, and cofactor. The movement of the deoxyadenosine moiety during the homolysis step positions the resulting 5'-deoxyadenosyl radical for the subsequent hydrogen atom transfer from the substrate, methylmalonyl-CoA.
Kwiecien
Renata A
RA
Institute of Applied Radiation Chemistry, Technical University of Lodz, Poland.
Khavrutskii
Ilja V
IV
Musaev
Djamaladdin G
DG
Morokuma
Keiji
K
Banerjee
Ruma
R
Paneth
Piotr
P
D000241:Adenosine / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003038:Cobamides / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008765:Methylmalonyl-CoA Mutase / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D013816:Thermodynamics
D003038:Cobamides; D008765:Methylmalonyl-CoA Mutase; C000913:cobamamide; D000241:Adenosine