Methylmalonyl-CoA mutase, mitochondrial (MUT)

Methylmalonyl-CoA mutase (MUT) is a nuclear-encoded mitochondrial enzyme that plays a critical role in the catabolism of branched-chain amino acids (valine, isoleucine, threonine, methionine), odd-chain fatty acids, and cholesterol (UniProt P22033). It catalyzes the isomerization of L-methylmalonyl-CoA to succinyl-CoA, a key step in the entry of propionate-derived carbons into the citric acid cycle; this reaction requires adenosylcobalamin, a derivative of vitamin B12, as an essential cofactor (NCBI Gene ID: 4594). Mutations in the MUT gene lead to methylmalonic acidemia (MMA), a severe metabolic disorder characterized by the accumulation of toxic metabolites, leading to metabolic acidosis, developmental delays, and organ failure (OMIM #251000). Therapeutic strategies focus on restoring enzyme activity through high-dose cobalamin supplementation in responsive patients or through emerging modalities such as mRNA-3927, an mRNA therapy designed to induce cellular production of functional MUT protein (Moderna, 2023). Additionally, gene therapy candidates like LB-001 and HMI-103 aim to provide a functional copy of the MUT gene to hepatocytes to restore metabolic flux and reduce the systemic burden of methylmalonic acid (LogicBio, 2022; Homology Medicines, 2021). Despite these advancements, patients remain at risk for long-term complications including renal failure and neurological impairment, necessitating continuous monitoring of metabolic biomarkers.

Other names

MCMMethylmalonyl-CoA isomeraseMethylmalonyl-CoA mutaseMethylmalonyl-CoA mutase deficiency

Restoration of enzyme activity through high-dose cofactor supplementation (adenosylcobalamin), delivery of synthetic mRNA encoding the functional MUT protein, or genomic integration of a functional MUT gene via viral vectors (StatPearls, 2023; ClinicalTrials.gov NCT04899310).