Methylmalonyl COA mutase Vitamin B12- Dependent enzymes

Methylmalonyl-CoA Mutase catalyzes a molecular rearrangement in which the branched carbon chain of methylmalonyl- CoA is converted to the linear carbon chain of succinyl-CoA.

Coenzyme B12, a derivative of vitamin B12 (also called cobalamin), is the prosthetic group of Methylmalonyl- CoA Mutase.

Within the Methylmalonyl-CoA Mutase active site, the cobalt atom of coenzyme B12 has two axial ligands: the methyl C atom of 5'-deoxyadenosine (not shown here). an enzyme histidine 610 N

The carboxyl that is in ester linkage to the thiol of coenzyme A is shifted to an adjacent carbon atom, with opposite shift of a hydrogen atom.

The Co atom is coordinated by His 610 in the active site of the enzyme Page 925

AdoCb N-term C-term

L-methylmalonyl-CoA mutase, shifts the bonding of the -CO-CoA from C-2 to C-3, to give succinyl-CoA. This tricky C-C bond rearrangement is atypical in that it involves a radical mechanism.

The radical reaction is induced by the 5- deoxyadenosine cobalmin coenzyme complex (vitamin B12). Cobalt readily transforms between Co(III)- CH2Ado (fully bonded ligand) and Co(II) - -.CH2Ado (loosely complexed radical). The.CH2Ado radical can capture H. from the substrate by 1-electron transfer.

Methylmalonyl-CoA mutase Mechanism begins with homolytic cleavage of the C- Co(III) bond. The AdoCbl is a free radical generator C-Co(III) bond is weak and it is broken and the radical is stabilized favoring the formation of the adenosyl radical. Rearrangement to form succinyl-CoA from a cyclopropyloxy radical Abstraction of a hydrogen atom from 5’deoxyadenosine to regenerate the adenosyl radical Release of succinyl-CoA