Figure 1.

Vitamin B₁₂ metabolism. Dietary vitamin B₁₂ is transported through the digestive system and absorbed in the intestine where it binds to apo-transcobalamin (apo-TC) to form holotranscobalamin (holo-TC). Holo-TC is the bioactive form of vitamin B₁₂. Holo-TC reaches circulation and it is then taken up by all cells in the body via receptor-mediated endocytosis (the transcobalamin (TC) receptor is also known as CD320). Once in the cell, vitamin B₁₂ is freed from TC in the lysosome and exported into the cytosol. Downstream cytosolic processing and trafficking events ensure that vitamin B₁₂ ultimately reaches cytosolic methionine synthase and mitochondrial methylmalonyl-CoA mutase. Nutritional deficiency of vitamin B₁₂ blocks the reactions catalyzed by methionine synthase and methylmalonyl-CoA, resulting in the accumulation of their respective substrates, homocysteine (Hcy) and methylmalonyl-CoA (MMA-CoA). Hcy and MMA are toxic to cell metabolism; therefore, cells export these metabolites into circulation under conditions of B₁₂ deficiency. This manifests clinically as elevated concentration of Hcy and MMA in plasma or serum. A vascular endothelial cell is used as a generic model. This figure was modified from reference [19].