Transcobalamin transport

Food vitamin B 2 appears to bind to a saUvary transport protein referred to as the R-protein, R-binder, or haptocorrin. In the stomach, R-protein and the intrinsic factor competitively bind the vitamin. Release from the R-protein occurs in the small intestine by the action of pancreatic proteases, leading to specific binding to the intrinsic factor. The resultant complex is transported to the ileum where it is bound to a cell surface receptor and enters the intestinal cell. The vitamin is then freed from the intrinsic factor and bound to transcobalamin II in the enterocyte. The resulting complex enters the portal circulation. 

Transport. Transcobalamin II dehvers the absorbed vitamin 3 2 to cells and is the primary plasma vitamin B22-binding transport protein. It is found in plasma, spinal fluid, semen, and extracellular fluid. Many cells, including the bone marrow, reticulocytes, and the placenta, contain surface receptor sites for the transcobalamin II—cobalamin complex. 

Other plasma vitamin B 2 proteins, transcobalamines I and III, appear to have primarily a storage function and only a lesser role in transport. 

Mammalian intestinal absorption requires the presence of two receptors and two transporters, which is itself a unique feature. Specific transporters such as intrinsic factor, transcobalamin, and haptocorrin have been characterized,1113 as well as a number of receptors for passage across cell membranes. A number of biochemical studies on cell uptake1114 and receptors1115,1116 of cobala-mins have been reported. Genetic disorders that impair the synthesis, transport, or transmembrane passage of cobalamins and their consequences have been reviewed.1117,1118... 

Vitamin B12 (cyanocobalamin) is produced by bacteria B12 generated in the colon, however, is unavailable for absorption (see below). liver, meat, fish, and milk products are rich sources of the vitamin. The minimal requirement is about 1 pg/d. Enteral absorption of vitamin B 2 requires so-called intrinsic factor from parietal cells of the stomach. The complex formed with this glycoprotein undergoes endocytosis in the ileum. Bound to its transport protein, transcobalamin, vitamin B12 is destined for storage in the liver or uptake into tissues. 

Dietary forms of vitamin B12 are converted to active forms in the body. Vitamin B12, mainly from liver, eggs and dairy products, is absorbed in terminal ileum. Intrinsic factor from parietal cells is required for absorption. Vitamin B12 is transported in the blood by transcobalamin II and stored in the liver. These stores are such that generally a patient does not become symptomatic until some years after the onset of vitamin B12 deficiency. 

Once absorbed, vitamin B12 is transported to the various cells of the body bound to a family of specialized glycoproteins, transcobalamin I, II, and III. Excess vitamin B12 is transported to the liver for storage. 

Vitamin B12 can be absorbed when present in physiological amounts only if it is first bound to a specific protein—the so-called intrinsic factor—that tightly binds to the vitamin. The complex then passes through the jejunum to the ileum, which contains receptor sites for the vitamin B12/intrinsic factor complex. Calcium ions are required for the reaction between ileal receptors and the intrinsic factor/vitamin B12 complex. The reaction is inhibited by EDTA and reduced by a pH below 5.4. The vitamin appears to be separated from intrinsic factor at the ileal receptor sites and is then bound to another protein carrier, transcobalamin II, which transports the vitamin and permits its uptake by a number of tissues. The subject has been well reviewed by Jacob and her colleagues (Jl). Removal of 60 cm of ileum may impair vitamin B12 absorption and with the loss of 180 cm absorption is almost always affected. 

Figure 28-4. The enterohepatic circulation of vitamin B12. TCII (transcobalamin ID is the transport protein that carries newly absorbed dietary vitamin B12 from the intestine to tissues. Approximately 20% of circulating vitamin B12 is transported by TCII the remainder of vitamin B12 is bound toTCI.THF, tetrahydrofolate.

Altbougb transcobalamin II is tbe metaboUcaUy important pool of plasma vitamin B12, it accounts for only 10% to 15% of tbe total circulating vitamin. Tbe majority is bound to baptocorrin (also known as transcobalamin I). Tbe function of baptocorrin is not well understood it bas a relatively long balf-life (7 to 10 days), and does not seem to be involved in tissue uptake or intertissue transport of tbe vitamin. Altbougb genetic lack of transcobalamin 11 results in severe (and fatal) vitamin B12 deficiency, genetic lack of baptocorrin seems to bave no adverse effects. 

The human Bu-binder intrinsic factor is a glycoprotein of ca. 44kDa, with a high binding constant (in 1 1 complexes) for vitamin B12 (1) and other cobalamins. The intrinsic factor is secreted by cells of the gastric mucosa and specifically binds cobalamins and carries them to the ileum. There the ileum receptor protein accepts the corrinoid from the intrinsic factor complex and transports it further across the intestinal epithelial absorptive cell. The cobalamins then appear to be bound to transcobalamin II and transported in the blood in this way to membrane-bound transcobalamin/corrin receptor proteins of the specific cells. ... 

The daily requirement of cobalamin is about 3.0 micrograms. Absorption takes place mainly in the terminal ileum, and it is carried in plasma bound to proteins. Some 90% of recently absorbed or administered cobalamin is carried on transco-balamin II an important transport protein which is rapidly cleared from the circulation 6-9 minutes). Hereditary deficiency of transcobalamin II causes severe cobalamin deficiency. About 80% of all circulating cobalamin is bound to transcobalamin I (t) 9-12 days) which is possibly a plasma storage form (hereditary deficiency of which is of no consequence). Cobalamin in its reduced form... 

Transport. Transcobalamin II dehvers the absorbed vitamin B 2 to cells and is the primary plasma vitamin transport protein. It is... 

Following absorption the vitamin is transported to the liver in the blood bound to transcobalamin 11. 

Metabolism of cobalamins in mammalian cells. Note the compartmentalization of the synthesis of the two coenzymes adenosylcobalamin (AdoCbl) synthesis occurs in mitochondria, whereas that of methylcobalamin (MeCbl) occurs in cytoplasm. TCII, Transcobalamin II OH-Cbl, hydroxocobalamin T, transport protein for TCII-OHCbl complex FH4, MeFH4, tetrahydrofolate and methyltetrahydrofolate, respectively Cbl, a cobalamin in which the ligand occupying the sixth coordination position of the cobalt is not known. The numerical superscripts adjacent to some of the cobalamins indicate the oxidation state of the cobalt ion. Cobalamins in the +1, +2, and +3 oxidation states are also known as Bn, B 2, and Bi2j, respectively. 

Absorption, transport, and cellular uptake of vitamin B12 in humans. IF, Intrinsic factor TCII, transcobalamin II circles in the membranes of the ileal mucosal cell and peripheral tissues represent transport molecules for IF/B12 and TCII/B12. respectively. 

After the stomach s acidic environment facilitates the breakdown of vitamin B12 bound to food, the vitamin B12 binds to the intrinsic factor released by the stomach s parietal cells. The secretion of intrinsic factor generally corresponds to the release of hydrochloric acid and serves as a cell-directed carrier protein similar to transferrin for iron. This complex, resistant to degradation, forms in the duodenum and allows for subsequent absorption of vitamin B12 in the terminal ileum. The cobalamin-intrinsic factor complex is taken up into the ileal mucosal cell, the intrinsic factor is discarded, and the cobalamin is transferred to transcobalamin It, which serves as a transport protein. This complex is secreted into the circulation and is taken up by the fiver, bone marrow, and other cells. Transcobalamin 11 has a short half-fife of 1 hour and is rapidly cleared from the blood. Consequently, most circulating cobalamin is bound to serum haptocorrins (formerly transcobalamin I and transcobalamin IB) whose function is unknown. However, it should be noted that an alternate pathway for vitamin B12 absorption independent of intrinsic factor or an intact ter-... 

Dietary cobalamin is absorbed from animal food sources by a multistage process shown in Figure 42-2. Cobalamin absorption requires the presence of a protein (the intrinsic factor, IF) secreted from the parietal cells of the stomach to bind cobalamin and aid in its absorption in the ileum. The protein is released into the ileum while the cobalamin is transported to the blood stream where it binds specialized serum proteins, the transcobalamins (TC), which transport it to other tissues such as liver where cobalamin can be stored (usually several milligrams are present in liver). In the absence of the intrinsic factor... 

Figure 42-2. Absorption, transport and storage of vitamin Bj. IF = intrinsic factor, a glycoprotein secreted by gastric parietal cells TC = transcobalamins, blood proteins that carry cobalamin to the Uver. (Reproduced, with permission, from D.B. Marks, et al. Basic Medical Biochemistry A Clinical Approach. Philadelphia Lippincott Williams Wilkins, 1996 619.)...

D. Cobalamin is transported in the blood to tissues by proteins named transcobalamins... 

D. Cobalamin is transported in the blood by transcobalamins. Cyanocobalamin, the pharmacologic preparation of cobalamin available in vitamin pills, is an active as is. Cobalamin is not active with an iron cofactor. The intrinsic factor is produced by parietal cells in the stomach. Cobalamin must be reduced to the Co+ state for activity. 

Once absorbed, vitamin Bjj binds to transcobalamin II, a plasma /5-globulin, for transport to tissues. Two other transcobalamins (I and III) also are present in plasma their concentrations are related to the rate of turnover of granulocytes. They may represent intracellular storage proteins that... 

FIGURE 53-8 The absorption and distribution of vitamin Deficiency of vitamin can result from a congenital or acquired defect in any one of the following (1) inadequate dietary supply (2) inadequate secretion of intrinsic factor (classical pernicious anemia) (3) ileal disease (4) congenital absence of transcobalamin II (Tell) or (5) rapid depletion of hepatic stores by interference with reabsorption of vitamin excreted in bile. The utility of measurements of the concentration of vitamin B 2 tn plasma to estimate supply available to tissues can be compromised by liver disease and (6) the appearance of abnormal amounts of transcobalamins I and III (Tcl and III) in plasma. Finally, the formation of methylcobalamin requires (7) normal transport into cells and an adequate supply of folic acid as CH H PteGlu. ... 

The B12 within the enterocyte complexes with transcobalamin 11 and then is released into circulation. The transcobalamin II-B12 complex delivers B12 to the tissues, which contain specific receptors for this complex. The liver takes up approximately 50% of the vitamin B12, and the remainder is transported to other tissues. The amount of the vitamin stored in the liver is large enough that 3 to 6 years pass before symptoms of a dietary deficiency occur. 

F. 40.7. Absorption, transport, and storage of vitamin B12. Dietary B12 binds to R-binders (haptocorrins) in the stomach and travels to the intestine, where the R-binders are destroyed by pancreatic proteases. The freed B12 then binds to intrinsic factor (IF). B12 is absorbed in the ileum and carried by called transcobalamins (TC) to the hver, where B12 is stored. 

Vitamin B12 is synthesized in large quantities by the intestinal flora, particularly in ruminants. The exact amount of vitamin B12 required by the normal human is not known. The absorption of vitamin B12 from the gastrointestinal tract is dependent on the presence of a gastric mucoprotein called intrinsic factor. Calcium ions seem to be necessary for the interaction of vitamin B12 with this intrinsic factor. Vitamin B12, which is absorbed only in the ileum, is stored in the liver. There are two transport proteins for vitamin Bj2 transcobalamin I and II, the latter being physiologically more important. Vitamin B12 plays an important role in the metabolism of functional groups with one carbon atom such as the methyl group... 

An average supply of food with about 3-4 xg of vitamin B12 (1) is considered necessary for sustaining physical well being [148]. The proteins known to be involved in uptake and transport of cobalamin in humans are intrinsic factor (IF), transcobalamin (TC) and haptocorrin (HC) [148,259]. These three soluble proteins ensure that the needed amount of cobalamin reaches the two intracellular enzymes methionine synthase (in cytosol) and methylmalonyl-CoA mutase (in mitochondria) [148,260]. 

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