{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMMACHC was originally identified as the gene responsible for the most common inborn error of vitamin B₁₂ metabolism—cobalamin C (cblC) deficiency—manifesting as combined methylmalonic aciduria and homocystinuria. Genetic studies refined its chromosomal localization through linkage analyses and homozygosity mapping, and extensive mutation screening has revealed a broad spectrum of loss‐of‐function alleles whose genotype–phenotype correlations also influence the age of onset and clinical severity of the disease. In addition, novel epigenetic regulatory events at the MMACHC locus have been described that further complicate the disease presentation. These findings have greatly advanced prenatal and diagnostic testing for cblC disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical investigations have established that MMACHC functions as a versatile, cytosolic cobalamin trafficking chaperone that “processes” vitamin B₁₂ derivatives early in the intracellular pathway. In vitro and cellular studies demonstrate that MMACHC catalyzes a NADPH‐dependent reductive decyanation of cyanocobalamin—cleaving the cobalt–carbon bond to release cyanide—and also promotes dealkylation of other alkylcobalamins via a glutathione‐dependent nucleophilic displacement mechanism. These reactions convert the incoming cobalamins into a common intermediate, cob(II)alamin, which is then funneled into the biosynthesis of the two active coenzymes, methylcobalamin and adenosylcobalamin, needed by methionine synthase and methylmalonyl‐CoA mutase, respectively. Complementary structural and stability studies have revealed a nitroreductase‐like scaffold, a defined ligand–binding pocket (involving key arginine residues) and even dimerization upon cofactor binding—all features that are critical for its catalytic turnover and therapeutic responsiveness in cblC patients."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, MMACHC functions within a broader network of vitamin B₁₂‐processing proteins by engaging in specific protein–protein interactions that ensure the efficient delivery of cob(II)alamin to downstream targets. Its interaction with MMADHC, for example, appears to guide the bifurcation of cobalamin trafficking toward the cytosolic and mitochondrial pathways, ensuring that the cofactor is readily available to methionine synthase and methylmalonyl‐CoA mutase. Structural mapping and binding studies, as well as investigations into altered protein interactions in disease states, have provided key insights into how defects in MMACHC, or its failure to interact appropriately with partners such as MMADHC and others, contribute to the metabolic derangements observed in cblC disorder."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jordan P Lerner-Ellis, Jamie C Tirone, Peter D Pawelek, et al. 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