methylmalonylCoA

Methylmalonyl-CoA is a coenzyme A thioester of methylmalonic acid and serves as an intermediate in propionate metabolism. It is formed from propionyl-CoA during the catabolism of odd-chain fatty acids and certain amino acids, including valine, isoleucine, methionine, and threonine. Propionyl-CoA carboxylase, a biotin-dependent enzyme, converts propionyl-CoA to D-methylmalonyl-CoA, which is then epimerized by methylmalonyl-CoA epimerase to L-methylmalonyl-CoA.

L-methylmalonyl-CoA is rearranged by methylmalonyl-CoA mutase, a B12-dependent enzyme, to succinyl-CoA, which enters the citric acid cycle. The essential cofactor for the mutase is adenosylcobalamin (coenzyme B12). Defects in this pathway lead to accumulation of methylmalonyl-CoA and methylmalonic acid, with elevated levels detectable in blood and urine.

Clinical significance: Inborn errors of metabolism such as methylmalonic acidemia result from mutations in MUT or defects in cobalamin metabolism. Patients may present with metabolic acidosis, hyperammonemia, poor feeding, developmental delay, and organ dysfunction. Diagnosis is often aided by newborn screening or analysis of methylmalonic acid in plasma or urine. Management varies by etiology and may include dietary restriction of propionate precursors, vitamin B12 supplementation in responsive forms, carnitine to enhance excretion, and antibiotics to reduce gut propionate production; severe cases may require intensive supportive care.