Methylmalonic aciduria and homocystinuria type C protein (MMACHC)

Methylmalonic aciduria and homocystinuria type C protein (MMACHC) is a cytosolic enzyme essential for intracellular vitamin B12 (cobalamin) metabolism[1][3][4]. It catalyzes the decyanation of cyanocobalamin and dealkylation of alkylcobalamins—essential early steps that provide the active cofactor forms, adenosylcobalamin and methylcobalamin, used by methylmalonyl-CoA mutase in mitochondria and methionine synthase in cytosol[1][3]. MMACHC functions as a trafficking chaperone, directing vitamin B12 derivatives to cellular compartments where B12-dependent enzymes operate. Genetic defects in MMACHC cause combined methylmalonic acidemia with homocystinuria (cblC deficiency), the most common inborn error of B12 metabolism, which manifests with neurodevelopmental, hematologic, and multisystem disease. Biochemical hallmarks include hyperhomocysteinemia, elevated methylmalonic acid, and reduced methionine[4]. Clinical management relies mainly on high-dose forms of vitamin B12, particularly hydroxocobalamin, but therapeutic response varies and may not fully reverse symptoms[4]. MMACHC is not a classical receptor or signaling enzyme, but its fundamental enzyme-chaperone role in essential cofactor processing establishes it as a valid molecular and therapeutic target in rare metabolic disorders[1][2][3][4].

Other names

CblC proteinCyanocobalamin reductase (cyanide-eliminating)Alkylcobalamin dealkylaseMetabolism of cobalamin associated CMethylmalonic aciduria (cobalamin deficiency) cblC type, with homocystinuriaAlkylcobalamin:glutathione S-alkyltransferaseMMACHC gene productcblC

Vitamin/cofactor supplementation to bypass defective processing (hydroxocobalamin, methylcobalamin); Restoration of biochemical pathways dependent on B12-derived cofactors