Methylmalonyl-CoA mutase

Methylmalonyl-Coenzyme A mutase is an enzyme involved in key metabolic pathways. It catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA. It requires its Vitamin B derived prosthetic group, adenosylcobalamin, to function.

The substrate of Methylmalonyl-CoA mutase, methylmalonyl-CoA, is primarily derived from propionyl-CoA, a substance formed from the catabolism and digestion of isoleucine, valine, threonine, methionine, thymine, uracil, cholesterol, or odd-chain fatty acids.

The product of the enzyme, succinyl-CoA, is a key molecule of the TCA cycle.

Pathology
A deficiency of this enzyme is responsible for an inherited disorder of metabolism, Methylmalonyl-CoA mutase deficiency, which is one of the causes of methylmalonic acidemia.

Function
MUT resides in the mitochondria where a number of substances, including the branched-chain amino acids Ile and Val, as well as Met, Thr, thymine and odd-chain FAs are metabolized via Methylmalonate semialdehyde (MMlSA) or Propionyl-CoA (Pr-CoA) to a common compound - Methyl-malonyl-CoA (MMl-CoA).

MUT reaction mechanism begins with homolytic cleavage of AdoB12's C-Co(III) bond, the C and Co atoms each acquire one of the electrons that formed the cleaved electron pair bond. The Co ion therefore fluctuates between its Co(III) and Co(II) oxidation states [the two states are spectroscopically distinguishable: Co(III) is red and diamagnetic (no unpaired electrons), whereas Co(II) is yellow and paramagnetic (unpaired electrons)]. Hence, the role of coenzyme B-12 in the catalytic process is that of a reversible free radical generator. The C-Co(III) bond is well suited to this function because it is inherently weak (dissociation energy = 109 kJ/mol) and appears to be further weakened through steric interactions with the enzyme. A homolytic cleavage reaction is unusual in biology; most other biological bond cleavage reactions occur via heterolytic cleavage (in which the electron pair forming the cleaved bond is fully acquired by one of the separating atoms). (p.)