Intrinsic factor vitamin B12 complex

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. 

About 70% of patients also have antiintrinsic factor antibodies in plasma, saliva, and gastric juice. These canbe either blocking antibodies, which prevent the binding of vitamin B12 to intrinsic factor, or precipitating antibodies, which precipitate both free intrinsic factor and intrinsic factor-vitamin B12 complex. Some patients have both types of antiintrinsic factor antibody. Although the oral administration of partially purified preparations of intrinsic factor will restore the absorption of vitamin B12 in many patients withpernicious anemia, this can eventually result in the production of antiintrinsic factor antibodies, so parenteral administration of vitamin B12 is the preferred means of treatment. 

Cooper and Castle have proposed a three-step sequence to explain the vitamin B12 absorption in the gastrointestinal tract. In the first step, vitamin B12 binds with the intrinsic factor in gastric juice. The affinity of the vitamin for the intrinsic factor is thought to be greater than its affinity for proteins in the intestinal content consequently, the intrinsic factor (IF) successfully displaces the vitamin from its weaker bonds with other proteins. Calcium facilitates and EDTA inhibits the absorption of vitamin B12 by the everted intestine. On the basis of these and related findings, workers proposed the second step in vitamin Bi2 absorption. At that stage it is assumed that the intrinsic factor-vitamin B12 complex is trapped in the intestinal wall by the intermediate of calcium bonds and absorbed by pinocytosis. This stage of the absorption process probably is interfered with in sprue and steatorrhea where calcicum soaps are formed in the intestinal lumen. 

The possibility that the intrinsic factor-vitamin B12 complex is absorbed per se cannot be excluded simply on the basis that the intrinsic factor is a protein, since it is known that proteins such as ribonuclease enter the cell. 

Bi2 are only about 2 meg, it would take about 5 years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if Bi2 absorption were stopped. Vitamin B12 in physiologic amounts is absorbed only after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa. Intrinsic factor combines with the vitamin Bi2 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor-vitamin Bi2 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system. Vitamin Bi2 deficiency in humans most often results from malabsorption of vitamin B12 due either to lack of intrinsic factor or to loss or malfunction of the specific absorptive mechanism in the distal ileum. Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products. 

Vitamin B12 complex by guinea pig ileal mucosa in organ culture after in vivo incubation with intrinsic factor—vitamin B12. Br. J. Haematol. 40, 401-414 (1978). 

A few substances are so large or impermeant that they can enter cells only by endocytosis, the process by which the substance is bound at a cell-surface receptor, engulfed by the cell membrane, and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released inside the cytosol by breakdown of the vesicle membrane. Figure 1-5D. This process is responsible for the transport of vitamin B12, complexed with a binding protein (intrinsic factor) across the wall of the gut into the blood. Similarly, iron is transported into hemoglobin-synthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the transport proteins must be present for this process to work. 

A modified technique permits determination of the absorption in the presence and absence of exogenous intrinsic factor at the same time, by giving intrinsic factor-[ Co] vitamin B12 complex and free [ Co]vitamin B12 together, and measuring the relative amounts of each isotope excreted in the urine. 

The vitamin B12 receptor which facilitates uptake of the vitamin-intrinsic factor vitamin-binding protein complex has been used to enhance oral delivery and gastrointestinal uptake of peptides and proteins as their vitamin B12 conjugates (37). Commercial efforts are under way to exploit this receptor as well as the fetal Pc receptor which facilitates intestinal uptake of antibodies from colostrum/milk (38) and the polymeric immunoglobulin receptor which facilitates the serosal to mucosal transport of IgA and IgM (39). 

Vitamin B12 is special in as far as its absorption depends on the availability of several secretory proteins, the most important being the so-called intrinsic factor (IF). IF is produced by the parietal cells of the fundic mucosa in man and is secreted simultaneously with HC1. In the small intestine, vitamin B12 (extrinsic factor) binds to the alkali-stable gastric glycoprotein IF. The molecules form a complex that resists intestinal proteolysis. In the ileum, the IF-vitamin B 12-complex attaches to specific mucosal receptors of the microvilli as soon as the chymus reaches a neutral pH. Then either cobalamin alone or the complex as a whole enters the mucosal cell. 

Intrinsic factor is produced by the parietal cells. Within the stomach, it combines with vitamin Bu to form a complex necessary for absorption of this vitamin in the ileum of the small intestine. Vitamin B12 is an essential factor in the formation of red blood cells. Individuals unable to produce intrinsic factor cannot absorb vitamin B12 and red blood cell production is impaired. This condition, referred to as Pernicious anemia, occurs as a result of an autoimmune disorder involving destruction of parietal cells. 

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. 

Severe cyanocobalamin (vitamin B12) deficiency results in pernicious anemia that is characterized by megaloblastic anemia and neuropathies. The symptoms of this deficiency can be masked by high intake of folate. Vitamin B12 is recycled by an effective enterohep-atic circulation and thus has a very long half-hfe. Absorption of vitamin B12 from the gastrointestinal tract requires the presence of gastric intrinsic factor. This factor binds to the vitamin, forming a complex that... 

Vitamin B12. Vitamin B12 is a larger molecule than the other vitamins, and it can be absorbed via the intestine, which involves binding to specialized transport proteins.44 After oral administration, vitamin B12 binds to intrinsic factor (IF) produced from the parietal cells in the stomach and proximal cells in the duodenum. The vitamin B12—IF complex passes down the small intestine until it reaches the ileum, where the complex binds to a specific IF receptor located on the apical membrane of the villous enterocyte. The complex is then internalized via RME, vitamin B12 is released from IF by the action of cathepsin L on IF, and free vitamin B12 consequently forms the complex with transcobal-amin II to be delivered into the basolateral side of the membrane via the transcytotic pathway. 

Facilitated transport is essentially the same as carrier-mediated transport, except that besides a carrier molecule, another transport facilitator is essential. For example, vitamin B12 attaches to the intrinsic factor, and the vitamin B12-intrinsic factor complex then attaches to the carrier molecule and is transported. This transport process does not require energy and does not proceed against a concentration gradient (Figure 1.3). 

Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12-intrinsic factor complex is damaged, as when the ileum is involved with inflammatory bowel disease, or when the ileum is surgically resected. In these situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added. Other rare causes of vitamin B,2 deficiency include bacterial overgrowth of the small bowel, chronic pancreatitis, and thyroid disease. Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor and congenital selective vitamin Bi2 malabsorption due to defects of the receptor sites in the distal ileum. 

Water-soluble vitamins are absorbed by special transport proteins, some require active transport, others facilitated diffusion in order to cross the gastric lumen. Vitamin B12 cannot be absorbed by itself it has to be bound to intrinsic factor which is secreted into the lumen of the stomach by the parietal cells. Intrinsic factor binds to vitamin B12 to form a complex that is subsequently absorbed in the ileum. 

Patients with B12 deficiency often have problems absorbing the vitamin. The gastric mucosa secretes an intrinsic factor which binds B12 to form a complex, allowing absorption in the ileum. When secretion of intrinsic factor is diminished, B12 absorption is reduced, for example in gastric cancers, inflammatory states, trauma or surgery. 

As the name suggests, cyanocobalamin (vitamin B12) is a compound of cobalt (Co(lll)). With a complex organic structure, this essential water-soluble vitamin is obtained from dietary animal sources and is required for deoxyribonucleic acid (DNA) synthesis, where enzymes that use vitamin B12 are involved in the transfer of one-carbon units. The absorption of this vitamin from the gastrointestinal tract only occurs when intrinsic factor glycoprotein is present. While the body can store up to a 12-month supply of vitamin B12, rapid growth or conditions causing rapid cell turnover can increase the body s requirement for this vitamin. 

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. ... 

FIGURE 2.23 The absorption of vitamin B12, an event dependent on intrinsic factor. The absorption of vitamin B12 from the gut and its delivery to various cells of the body involves the following steps. (1) Vitamin B12 is liberated from meat. (2) Intrinsic factor is secreted from parietal cells in the stomach. (3) A tight complex between intrinsic factor and the vitamin is formed. (4) The complex travels to the ileum, where the vitamin dissociates from the intrinsic factor at the membrane of the enterocyte. (5) Transcobalamin, a protein circulating in tire blood, forms a complex with the vitamin. (6) The complex travels to various organs, diffuses from the capillary to the plasma membrane of a cell, and is boimd by receptor proteins. The complex is then taken into the cell by endocytosis. 

Because dietary vitamin B12 is protein bound, the first step in absorption is its release in the stomach. Release is enhanced by gastric pH and pancreatic proteases. The freed vitamin is bound immediately to a glycoprotein, the intrinsic factor, secreted by parietal cells of the gastric mucosa. The vitamin Bi -intrinsic factor complex is carried to the intestines, where it binds with receptors in the ileum. Absorption is mainly by an active proccs.s, which can be saturated by 1.3 to 3 /eg of vitamin B, Excess amounts may be absorbed passively. 

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