Methylmalonyl-CoA mutase, mitochondrial (MMUT) (MMUT)

Methylmalonyl-CoA mutase (MMUT) is a nuclear-encoded mitochondrial enzyme essential for the degradation of branched-chain amino acids (valine, isoleucine, threonine, and methionine), odd-chain fatty acids, and the side chain of cholesterol (UniProt P22033). It catalyzes the reversible isomerization of (R)-methylmalonyl-CoA to succinyl-CoA, which then enters the Krebs cycle for energy production (NCBI Gene ID 4594). This enzymatic process is strictly dependent on adenosylcobalamin, a derivative of vitamin B12, which serves as a radical-generating cofactor (PubMed: 11134021). Deficiency in MMUT activity, often due to genetic mutations, results in methylmalonic acidemia (MMA), a life-threatening condition characterized by the accumulation of methylmalonic acid and other toxic metabolites (StatPearls: NBK448075). Current therapeutic interventions include dietary restriction, vitamin B12 supplementation for responsive variants, and innovative approaches like mRNA-based therapies (e.g., mRNA-3928) and gene editing (e.g., LB-001) designed to restore functional enzyme levels in the liver (ClinicalTrials.gov: NCT04899310). These emerging therapies aim to provide a long-term solution by enabling the body to produce functional MMUT protein, thereby reducing toxic metabolite levels and preventing metabolic crises.

Other names

MCMMethylmalonyl-CoA isomeraseMUTMMUTMethylmalonyl-CoA mutase mitochondrial

Restoration of enzyme activity through cofactor supplementation to enhance residual function, mRNA-mediated protein expression in hepatocytes, or genomic integration of a functional gene copy (PubMed: 30111750; ClinicalTrials.gov: NCT04899310).