Intestines cobalamins

F6. Fyfe, J. C., Ramanujam, K. S., Ramaswamy, K., Patterson, D. F., and Seetharam, B., Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption. J. Biol. Chem. 266,4489-4494 (1991). 

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. 

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... 

Very small amounts of cobalamin are required each day (<5 i.g) and the diet normally provides plenty more than the minimum, so dietary B12 deficiency is uncommon, except in very strict vegetarians. Pernicious anaemia arises when a defect in the stomach results in too little secretion of a protein called intrinsic factor, without which, cobalamin cannot be absorbed in the ileum of the small intestine. 

Bi2 (cobalamin) Meat, fish, poultry, milk and milk products produced also by bacteria in the large intestine Nucleotide metabolism... 

Vitamin B12 (cobalamine) is one of the most complex low-molecular-weight substances occurring in nature. The core of the molecule consists of a tetrapyrrol system (corrin), with cobalt as the central atom (see p. 108). The vitamin is exclusively synthesized by microorganisms. It is abundant in liver, meat, eggs, and milk, but not in plant products. As the intestinal flora synthesize vitamin B12, strict vegetarians usually also have an adequate supply of the vitamin. 

Cobalamine can only be resorbed in the small intestine when the gastric mucosa secretes what is known as intrinsic factor—a glycoprotein that binds cobalamine (the extrinsic factor) and thereby protects it from degradation. In the blood, the vitamin is bound to a special protein known as trans-cobalamin. The liver is able to store vitamin Bi2 in amounts suf cient to last for several months. Vitamin B12 deficiency is usually due to an absence of intrinsic factor and the resulting resorption disturbance. This leads to a disturbance in blood formation known as pernicious anemia. 

Cobalt in small amounts is an essential element associated with vitamin B12, but at high levels can be toxic. There are no daily recommended intake levels for cobalt. Intestinal bacteria use cobalt to produce cobalamin, which in turn is an essential component of vitamin B12. Industrially, cobalt is used in pigments, permanent magnets, and as an alloy to harden metals as in tungsten carbide blades or drills. 

The effects of cobalamin deficiency are most pronounced in rapidy dividing cells, such as the erythropoietic tissue of bone marrow and the mucosal cells of the intestine. Such tissues need both Die N5-N10-methylene and N10-formyl forms of tetrahydrofolate for Ihe synthesis of nucleotides required for DNA replication (see pp. 291, 301). However, in vitamin B12 deficiency, the N5-methyl form of tetrahydrofolate is not efficiently used. Because the methylated fonn cannot be converted directly to other forms of tetrahydrofolate, tie Ns-methyl form accumulates, whereas the levels of the other forms decrease. Thus, cobalamin deficiency is hypothesized to lead to a deficiency of the tetrahydrofolate forms needed in purine and thymine synthesis, resulting in the symptoms of megaloblastic anemia. 

Alsenz, J., Russell-Jones, G. J., Westwood, S., et al. Oral absorption of peptides through the cobalamin (vatamin B12) pathway in the rat intestine. Pharm. Res. 17 825-832, 2000. 

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. ... 

Cobalamin is not significantly metabolised and passes into the bile (there is enterohepatic circulation which can be interrupted by intestinal disease and hastens the onset of clinical deficiency), and is excreted via the kidney. Body stores amount to about 5 mg (mainly in the liver) and are sufficient for 2-4 years if absorption ceases. 

Homocysteine is metabolized in the liver, kidney, small intestine and pancreas also by the transsulfuration pathway [1,3,89]. It is condensed with serine to form cystathione in an irreversible reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine-synthase. Cystathione is hydrolyzed to cysteine that can be incorporated into glutathione or further metabolized to sulfate and taurine [1,3,89]. The transsulfuration pathway enzymes are pyridoxal-5-phosphate dependent [3,91]. This co-enzyme is the active form of pyridoxine. So, either folates, cobalamin, and pyridoxine are essential to keep normal homocysteine metabolism. The former two are coenzymes for the methylation pathway, the last one is coenzyme for the transsulfuration pathway [ 1,3,89,91 ]. 

Cobalt has no confirmed nutritional role in mammalian organisms aside from its participation in the corrin ring structure of cobalamins (vitamin B12). Nonetheless, inorganic cobalt is absorbed by the intestine. That this absorption pathway was shared with iron was first suggested by the observation of a mineral-mineral competition 42). The use of radioisotopes of iron in diagnostic tests of absorption for characterizing iron nutrition in human subjects has been advanced (43-45). An excellent correlation between absorption of radioiron and radiocobalt has been reported (43-45). 

Intestinal malabsorption of vitamin B12 may be caused by gastrectomy or ileal resection, with an inverse relationship between the length of ileum resected and the absorption of vitamin B12. Other causes of malabsorption are tropical sprue, inflammatory disease of the small intestine, intestinal stasis with overgrowth of colonic bacteria, which consume the vitamin 6,2 ingested by the host, and HIV infection. Another cause of vitamin B malabsorption is failure to extract cobalamin from food. Some patients fail to absorb cobalamin bound to food, whereas absorption of nonfood-bound cobalamin in the Schilling test is unimpaired. This is particularly a problem in patients with compromised gastric status or early in the course of development of pernicious anemia. 

A large number of disorders are associated with cobalamin deficiency in infancy or childhood. Of these, the most commonly encountered is the Imerslund-Graesbeck syndrome, a condition that is characterized by inability to absorb vitamin B,2, with or without IF, and proteinuria. It appears to be due to an inability of intestinal mucosa to absorb the vitamin B,2 IF complex. The second most common of these is congenital deficiency of gastric secretion of IF. Very rarely, congenital deficiency of vitamin B12 in a breast-fed infant is due to deficiency of vitamin B12 in maternal breast milk as a result of unrecognized pernicious anemia in the mother. This is rare because most women with undiagnosed and untreated pernicious anemia are infertile. Additionally, there are some rare methylmalonic acidemias (acidurias) caused by inborn errors in homocysteine and methionine metabolism that are responsible for disorders in vitamin B status. ... 

Cobalt (Co) is essential for humans only as an integral part of vitamin (cobalamin). No other function for cobalt in the human body is loiown. Details of vitamin biochemistry and function are discussed above. Microflora of the human intestine cannot use cobalt to synthesize physiologically active cobalamin. The human vitamin B12 requirement must be supplied by the diet. Free (nonvitamin B12) cobalt does not interact with the body vitamin B12 pool. 

Cobalamin <5Mg Megaloblastic anemia Decreased intestinal absorption... 

Intestinal Receptor for IF-B 2 Complex. Although this receptor is not, strictly speaking, a cobalamin-binding protein, it is essential for normal absorption of dietary cobalamin. It is present on the membrane of microvilli of ileal but not jejunal or duodenal cells, with the highest concentration in the distal 60-cm portion of the small intestine. The purified receptor is composed of two subunits (M.W. 90,(X)0 and 140,000) and binds free IF and IF-B12 complex, although free IF binds more slowly. Subsequent transport of cobalamin into enterocytes is accomplished by an active process. 

B. Megaloblastic anemia is caused by a decrease in the synthesis of deoxythymidylate and the purine bases usually caused by a deficiency in either THF or cobalamin or both. This results in decreased DNA synthesis, which results in abnormally large hematopoietic cells created by perturbed cell division and DNA replication and repair. This patient exhibits signs of chronic alcoholism, which often leads to a folate deficiency. This can occur due to poor dietary intake, decreased absorption of folate due to damage of the intestinal brush border cells and resulting conjugase deficiency, and poor renal resorption of folate. 

Cobalamin (vitamin Bj ) deficiency Inadequate uptake of cobalamin from the diet often due to lack of intrinsic factor an intestinal transport protein or less often due to unaugmented vegetarian diet that strictly avoids meat or meat products, the source of dietary cobalamin. 

Approximately 3 jig of cobalamins is secreted into bile each day, 50-60% of which is not destined for reabsorption. This enterohepatic cycle is important because interference with reabsorption by intestinal disease can progressively deplete hepatic stores of the vitamin. This process may help explain why patients can develop vitamin Bj deficiency within 3-4 years of major gastric surgery, even though a daily requirement of 1-2 jig would not be expected to deplete hepatic stores of more than 2-3 mg during this time. 

Pernicious anemia, a deficiency of intrinsic factor, is a relatively common problem caused by malabsorption of dietary cobalamin. It may result from an inherited defect that leads to a decreased ability of gastric parietal cells to synthesize intrinsic factor or from partial resection of the stomach or of the ileum. Production of intrinsic factor often declines with age and may be low in elderly individuals. An alternative circumstance that leads to the development of a B12 deficiency is pancreatic insufficiency or a high intestinal pH, which would result from too little acid being produced by the stomach. Both of these conditions prevent the degradation of the R-binder-B12 complex as a result, B12 will not be released from the R-binder protein and, therefore, cannot bind to intrinsic factor. 

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