MMACHC, also known as CblC, encodes a protein crucial for intracellular vitamin B12 metabolism. Vitamin B12 obtained from the diet in forms like hydroxocobalamin, methylcobalamin, and adenosylcobalamin needs processing by MMACHC. This involves removing the upper-axial ligand to yield cob(II)alamin, which is then delivered to the B12-dependent enzymes methionine synthase and methylmalonyl-CoA mutase to regenerate the coenzyme forms MeCbl and AdoCbl. MMACHC thus plays a vital role in maintaining normal cellular functions related to B12-dependent metabolic pathways [1].

Mutations in MMACHC lead to cblC disease, the most common inborn error of B12 metabolism. In a mouse model with a gene-trap insertion in intron 1 of the Mmachc gene (Mmachc(Gt(AZ0348)Wtsi)), heterozygous mice showed reduced MMACHC protein and elevated homocysteine and methylmalonic acid levels. Homozygous Mmachc(Gt) embryos were not found after embryonic day 3.5 and could not generate giant cells in outgrowth assays, suggesting an early requirement for Mmachc in mouse development [2].

In conclusion, MMACHC is essential for processing vitamin B12 within cells, enabling the proper function of key B12-dependent enzymes. The study of Mmachc gene-modified mouse models has revealed its importance in early embryonic development, and its mutations are closely associated with cblC disease, highlighting its significance in understanding the pathophysiology of this inborn error of metabolism.

References:

1. Hannibal, Luciana, Jacobsen, Donald W. 2022. Intracellular processing of vitamin B12 by MMACHC (CblC). In Vitamins and hormones, 119, 275-298. doi:10.1016/bs.vh.2022.02.001. https://pubmed.ncbi.nlm.nih.gov/35337623/

2. Moreno-Garcia, Maira A, Pupavac, Mihaela, Rosenblatt, David S, Tremblay, Michel L, Jerome-Majewska, Loydie A. 2014. The Mmachc gene is required for pre-implantation embryogenesis in the mouse. In Molecular genetics and metabolism, 112, 198-204. doi:10.1016/j.ymgme.2014.05.002. https://pubmed.ncbi.nlm.nih.gov/24889031/