Transcobalamin II: ProductsTranscobalamin II (TCII) is an approximately 44 kDa protein that serves as a circulating carrier for cobalt-containing Vitamin B12 (also known as Cobalamin, or Cbl). Vitamin B12 plays an important role as a coenzyme during amino acid and nucleotide metabolism. Chronic deficiency of Vitamin B12 intake, absorption, or transport leads to serious health risks including megaloblastic anemia and neurologic symptoms. Prior to its interaction with TCII, dietary Vitamin B12 is bound by salivary Transcobalamin I (Haptocorrin) which shields it from the acidic environment of the stomach. Vitamin B12 is subsequently transferred to Transcobalamin III (also known by its traditional name Intrinsic Factor, or IF) following the proteolytic degradation of Transcobalamin I in the small intestine. Transcobalamin III-Vitamin B12 complexes are internalized into intestinal epithelial cells (IEC) by Cubam, which is a receptor complex containing the proteins Cubilin and Amnionless. IF is degraded within the IEC, while free Vitamin B12 is transcytosed and actively pumped across the basolateral membrane by the efflux transporter MRP1. Here, Vitamin B12 is picked up by TCII, which is secreted by vascular endothelial cells into the interstitial space between IEC. TCII binds to free Vitamin B12 with high affinity and is critical for the passage of Vitamin B12 into the blood stream. Circulating TCII-Vitamin B12 complexes are bound and internalized by the widely expressed TCII Receptor, also known as CD320 and 8D6A. A soluble form of CD320 circulates in the serum. TCII is then degraded intracellularly, and Vitamin B12 can function as a cofactor for methionine synthase and methylmalonyl-CoA mutase. In the kidney, TCII-Vitamin B12 complexes are filtered and reabsorbed through interactions with Megalin on proximal tubule epithelial cells. Megalin also directly interacts with CD320 in these cells . CD320 is additionally expressed on placental membranes for Vitamin B12 delivery to the developing fetus. Mature human TCII shares 74% amino acid (aa) sequence identity with mouse and rat TCII. Alternative splicing of human TCII generates a short isoform with a 27 aa internal deletion.