Proteins intrinsic factors

Nutritional Deficiency-Related Dementias. We have already mentioned that chronic alcoholics are subject to thiamine deficiency that can cause dementia. It usually occurs only after heavy, prolonged abuse of alcohol. In developed countries, the other key nutritional concern is vitamin deficiency. Vitamin deficiency can surprisingly strike even those with a healthy diet. Such people are missing a vital protein, intrinsic factor, which would enable them to absorb it from their digestive tract. 

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. 

Cobalamin binding protein Intrinsic factor of Castle... 

There are three classes of vitamin B12 binding proteins intrinsic factor, which facilitates absorption of the vitamin from the ileum R-proteins, which include TC I and TC III (the function of these proteins is not clear, but they probably act as mobile storage forms) and TC II, which is the transport protein responsible for carrying the vitamin to the tissues. Abnormalities of intrinsic factor or TC II could be expected to have serious consequences for the patient, and in recent years a number of such abnormalities have been reported. 

Another approach is to measure the redox potential at different temperatures and to calculate AH° and AS0. However, these thermodynamic terms also depends on both protein intrinsic factors and solvent reorganization effects. In general, the... 

Bi2 Binding Proteins. Bi2-binding (and Bi2-transporting) proteins are important in human, animal, and bacterial metabolism, where they function as extracellular, membrane-bound, and intracellular proteins. Lack of the B12-binding (extracellular) protein intrinsic factor and, as its consequence, a disorder in the uptake of vitamin B12 derivatives from the nutrition, is the most widely distributed cause for pernicious anemia (51,52). 

Acridium ester based chemiluminescence system was applied in food analysis with an acridium ester labelled vitamin derivative and the most specific vitamin B12 binding protein, intrinsic factor (IF) (Emi et al. 2006 Watanabe et al. 1998). The system was used in food analysis for shellfish and spirulina, and compared well with the microbiological method. 

In 1929, Castie (7) tied the work of Combe and Addison with that of Whipple, Miaot, and Murphy by ptoposiag that both an extrinsic factor and an intrinsic factor ate iavolved ia the coatrol of pernicious anemia. The extrinsic factor, from food, is vitamin 2- Th intrinsic factor is a specific B22-biading protein secreted by the stomach. This protein is requited for vitamin B 2 absorption. 

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. 

Also, the outcome covers a large spectrum. Autoantibodies can specifically block an important protein (such as the gastric intrinsic factor required for the uptake of orally taken vitamin B12), or the receptor for —> acetylcholine (as in myasthenia gravis), but also can... 

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. 

Hemostasis is the process that stops bleeding in a blood vessel. Normal hemostasis involves a complex process of extrinsic and intrinsic factors. Figure 44-1 shows the coagulation pathway and factors involved. The copulation cascade is so named because as each factor is activated it acts as a catalyst that enhances the next reaction, with the net result being a large collection of fibrin that forms a plug in the vessel. Fibrin is the insoluble protein that is essential to clot formation. 

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. 

There are several steps in the absorption of vitamin B. In the stomach and lumen of the small intestine it is hydrolysed from its (peptide) links with the proteins of which it is a component. It then attaches to gastric intrinsic factor, which is a glycoprotein of molecular mass about 50 000 kDa, to form a complex. This protects the vitamin from being damaged by acid in the stomach. The complex is carried into the ileum, where it binds to a receptor on the surface of the absorptive cells and is released from the intrinsic factor within the absorptive cell, hi the portal venous blood, it is transported to the liver bound to the vitamin B 12-binding protein, which also protects the vitamin. 

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. 

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. 

Pharmacokinetics The parietal cells of the stomach secrete intrinsic factor, which regulates the amount of vitamin B-12 absorbed in the terminal ileum. Bioavailability of oral preparations is approximately 25%. Vitamin B12 is primarily stored in the liver. Enterohepatic circulation plays a key role in recycling vitamin B-12 from mainly bile. If plasma-binding proteins are saturated, excess free vitamin B- 2 will be excreted in the kidney. 

Extrinsic pathway This pathway has fewer steps than the intrinsic pathway and occurs rapidly, within a matter of seconds if the trauma is severe. It is called the extrinsic pathway because a protein tissue factor, also called thromboplastin or coagulation factor III, takes into the blood stream from outside and initiates the formation of prothrombinase. Tissue factor is released from the surface of the damaged cells. It activates factor VII. Factor VII combines with factor X, activating it. Factor X in the presence of Ca combines with factor V to give active enzyme prothrombinase. 

Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide. Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins. Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans. Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the active forms. The ultimate source of vitamin Bi2 is from microbial synthesis the vitamin is not synthesized by animals or plants. The chief dietary source of vitamin Bi2 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products. Vitamin Bi2 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein normally secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12. 

Pernicious anemia is usually caused by poor absorption of the vitamin. Absorption depends upon the intrinsic factor, a mucoprotein (or rnuco-proteins) synthesized by the stomach lining.ad 1 Pernicious anemia patients often have a genetic predilection toward decreased synthesis of the intrinsic factor. Gastrectomy, which decreases synthesis of the intrinsic factor, or infection with fish tapeworms, which compete for available vitamin B12 and interfere with absorption, can also induce the disease. Also essential are a plasma membrane receptors 1 and two blood transport proteins... 

Detailed discussion of intrinsic fluorescence of proteins and factors that affect fluorescence emission by the aromatic amino acids (see pp. 618-663). 

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. 

M4. Moestrup, S. K., Kozyraki, R., Kristiansen, M., Kaysen, J. H., Rasmussen, H. H., Brault, D., Pontillon, F., Goda, F. O., Christensen, E. I., Hammond, T. G., and Verroust, P. J., The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J. Biol. Chem. 273, 5235—5242 (1998). 

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. 

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