title: Computational insights into the mechanism of radical generation in B12-dependent methylmalonyl-CoA mutase.
abstract: 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.
authors.affiliation: Institute of Applied Radiation Chemistry, Technical University of Lodz, Poland.
authors.forename: Renata A
authors.initials: RA
authors.lastname: Kwiecien
authors.forename: Ilja V
authors.initials: IV
authors.lastname: Khavrutskii
authors.forename: Djamaladdin G
authors.initials: DG
authors.lastname: Musaev
authors.forename: Keiji
authors.initials: K
authors.lastname: Morokuma
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
authors.forename: Piotr
authors.initials: P
authors.lastname: Paneth
mesh_terms: 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
chemical_list: D003038:Cobamides; D008765:Methylmalonyl-CoA Mutase; C000913:cobamamide; D000241:Adenosine