Methylmalonic aciduria and homocystinuria type C and D protein complex (MMACHC/MMADHC complex)

The MMACHC/MMADHC trafficking complex is a 1:1 heterodimeric protein assembly essential for the intracellular processing and distribution of vitamin B12 (cobalamin) [1, 10]. It consists of the Methylmalonic aciduria and homocystinuria type C protein (MMACHC), which acts as a multifunctional enzyme to dealkylate or decyanate incoming cobalamin, and the Methylmalonic aciduria and homocystinuria type D protein (MMADHC), which serves as a trafficking chaperone [1, 2, 11]. Together, they facilitate the conversion of dietary cobalamin into a common cob(II)alamin intermediate and partition it toward the synthesis of methylcobalamin in the cytosol and adenosylcobalamin in the mitochondria [1, 8, 13]. These cofactors are vital for the activity of methionine synthase and methylmalonyl-CoA mutase, respectively [2, 11, 16]. Genetic mutations in either component of the complex result in severe inborn errors of metabolism, such as cblC and cblD deficiencies, characterized by the accumulation of methylmalonic acid and homocysteine [3, 12, 15]. While current management relies on high-dose hydroxocobalamin and metabolic supplements, the complex is a primary target for emerging genomic therapies, including AAV-mediated gene replacement and mRNA-based interventions, aimed at restoring functional cobalamin trafficking and preventing progressive neurological and ocular complications [24, 33, 34].

Other names

cblC/cblD complexCobalamin trafficking chaperone complexMMACHC-MMADHC heterodimerIntracellular cobalamin trafficking complex

The complex facilitates the intracellular processing of cobalamin derivatives into active cofactors and their subsequent delivery to target enzymes [1, 8, 13].