TRANSCOBALAMIN-II AND THE MEMBRANE-RECEPTOR FOR THE TRANSCOBALAMIN-II-COBALAMIN COMPLEX

Vitamin B-12 (B-12, cobalamin (Cbl)) is a water soluble vitamin with a highly complex structure comprising a midplanar corrin ring composed of four pyrroline elements linked to a central cobalt atom (Hogenkamp, 1975). Above and below the corrin ring and attached to the cobalt ato m are, respectively, the upper axial ligand, which provides the co-fac tor function of the vitamin, and a lower axial Ligand, dimethylbenzimi dazole, which provides a steric configuration to the molecule that inf luences the binding affinity for the three Cbl-binding proteins, gastr ic intrinsic factor (IF), transcobalamin II (TCII) and transcobalamin I (TCI), also called haptocorrin (Hippe et al, 1971). Although a numbe r of different atoms or molecules can be substituted as the upper axia l ligand, only the 5'-deoxyadenosyl and the methyl adducts serve, resp ectively, as the co-factors for the enzymatic rearrangement of L-methy lmalonyl co-enzyme A (CoA) to succinyl CoA (Babior, 1975) and methylat ion of homocysteine for the de novo biosynthesis of methionine (Poston and Stadtman, 1975). The complex structure, hydrophilic property and size of Cbl precludes a facile mechanism by which the vitamin is trans ported across the cell membrane. Consequently, the intestinal absorpti on, plasma transport and uptake of Cbl by tissue cells in humans and m ost mammals is correspondingly compounded, requiring two secreted prot eins, IF and TCII as well as two membrane receptors. A receptor on the microvillus membranes of the mucosal cells of the terminal ileum bind s and internalizes the IF-Cbl complex by receptor-mediated endocytosis (Rothenberg et al, 1972; Kapadia et al, 1983). A receptor on tissue c ells is also necessary for the uptake of the TCII-Cbl complex by a sim ilar process of endocytosis (Youngdahl-Turner et al, 1978). In the abs ence of IF or TCII, or in the absence or (functional) impairment of th e two membrane receptors, Cbl deficiency will occur and this will impa ir synthesis of methionine (methyl-Cbl deficiency) and the rearrangeme nt of L-methylmalonyl CoA to succinyl-CoA (5' deoxyadenosyl-Cbl defici ency). The derangement of these pathways results in elevated levels of plasma homocysteine and methylmalonic acid, respectively (Lindenbaum et al, 1990). The clinical sequelae are megaloblastic anaemia with its consequences, and, frequently, an accompanying neuropsychiatric disor der characterized by demyelinization of the brain and long tracts of t he spinal cord, varying forms of dementia and peripheral neuropathy. T he objectives of this review are to summarize and update our knowledge about the properties of TCII and the TCII receptor on the plasma memb rane since these two proteins are essential for Cbl homeostasis. Altho ugh the primary function of TCII is to transport Cbl and promote its u ptake by cells, this protein also contributes to the intestinal absorp tion of Cbl and these interrelated functions will also be presented.