Intracellular processing of vitamin B₁₂ by MMACHC (CblC)

Vitamin B₁₂ (cobalamin, Cbl, B₁₂) is a water-soluble micronutrient synthesized exclusively by a group of microorganisms. Human beings are unable to make B₁₂ and thus obtain the vitamin via intake of animal products, fermented plant-based foods or supplements. Vitamin B₁₂ obtained from the diet comprises three major chemical forms, namely hydroxocobalamin (HOCbl), methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). The most common form of B₁₂ present in supplements is cyanocobalamin (CNCbl). Yet, these chemical forms cannot be utilized directly as they come, but instead, they undergo chemical processing by the MMACHC protein, also known as CblC. Processing of dietary B₁₂ by CblC involves removal of the upper-axial ligand (beta-ligand) yielding the one-electron reduced intermediate cob(II)alamin. Newly formed cob(II)alamin undergoes trafficking and delivery to the two B₁₂-dependent enzymes, cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MUT). The catalytic cycles of MS and MUT incorporate cob(II)alamin as a precursor to regenerate the coenzyme forms MeCbl and AdoCbl, respectively. Mutations and epimutations in the MMACHC gene result in cblC disease, the most common inborn error of B₁₂ metabolism, which manifests with combined homocystinuria and methylmalonic aciduria. Elevation of metabolites homocysteine and methylmalonic acid occurs because the lack of an active CblC blocks formation of the indispensable precursor cob(II)alamin that is necessary to activate MS and MUT. Thus, in patients with cblC disease, vitamin B₁₂ is absorbed and present in circulation in normal to high concentrations, yet, cells are unable to make use of it. Mutations in seemingly unrelated genes that modify MMACHC gene expression also result in clinical phenotypes that resemble cblC disease. We review current knowledge on structural and functional aspects of intracellular processing of vitamin B₁₂ by the versatile protein CblC, its partners and possible regulators.