methylmalonyl-CoA mutase

Methylmalonyl-CoA mutase catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA, using adenosylcobalamin (the active form of vitamin B12) as an essential cofactor. This reaction is a key step in the catabolism of odd-chain fatty acids, cholesterol, and the amino acids valine, isoleucine, methionine, and threonine—all of which are broken down via propionyl-CoA to methylmalonyl-CoA before entering the TCA cycle as succinyl-CoA.

Clinical significance: Vitamin B12 deficiency impairs this enzyme's function, leading to accumulation of methylmalonyl-CoA and its precursor, propionyl-CoA. This results in elevated serum and urine methylmalonic acid (MMA), which is a more specific marker of B12 deficiency than serum B12 levels alone (unlike folate deficiency, which does not elevate MMA). This distinction is clinically important because B12 deficiency also causes homocysteine elevation (due to impaired methionine synthase activity), while folate deficiency elevates only homocysteine, not MMA.

Inherited deficiency of methylmalonyl-CoA mutase itself (a rare autosomal recessive disorder) causes methylmalonic acidemia, presenting in infancy with metabolic acidosis, hyperammonemia, hypoglycemia, lethargy, vomiting, and failure to thrive. Treatment includes protein restriction (especially of the affected amino acids) and, if cobalamin-responsive, high-dose B12 supplementation.

Biochemical pathway: Propionyl-CoA carboxylase (biotin-dependent) converts propionyl-CoA to D-methylmalonyl-CoA, which is racemized to L-methylmalonyl-CoA, then converted by methylmalonyl-CoA mutase to succinyl-CoA, entering the TCA cycle—an important anaplerotic reaction.