Intrinsic factor
| Gastric intrinsic factor (vitamin B synthesis) | |||||||||||||
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 Rendering based on PDB 2CKT | |||||||||||||
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| Identifiers | |||||||||||||
| Symbols | GIF ; IF; IFMH; INF; TCN3 | ||||||||||||
| External IDs | OMIM: 609342 MGI: 1202394 HomoloGene: 3773 GeneCards: GIF Gene | ||||||||||||
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| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 2694 | 14603 | |||||||||||
| Ensembl | ENSG00000134812 | ENSMUSG00000024682 | |||||||||||
| UniProt | P27352 | P52787 | |||||||||||
| RefSeq (mRNA) | NM_005142 | NM_008118 | |||||||||||
| RefSeq (protein) | NP_005133 | NP_032144 | |||||||||||
| Location (UCSC) | Chr 11: 59.6 – 59.61 Mb | Chr 19: 11.75 – 11.76 Mb | |||||||||||
| PubMed search | |||||||||||||
Intrinsic factor (IF), also known as gastric intrinsic factor (GIF), is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 (cobalamin) later on in the small intestine.[1] In humans, the gastric intrinsic factor protein is encoded by the GIF gene.[2]
Haptocorrin (also known as HC, R protein, and transcobalamin I, TCN1), is a glycoprotein secreted by the salivary glands which binds to vitamin B12. Vitamin B12 is acid sensitive and in binding to transcobalamin I it can safely pass through the acidic stomach to the duodenum. Here in the less acidic environment of the small intestine, pancreatic enzymes digest the glycoprotein carrier and vitaminB12 can then bind to intrinsic factor. This new complex is then absorbed by the epithelial cells (enterocytes) of the ileum. Inside the cells, B12 dissociates once again and binds to another protein, transcobalamin II (TCN2). The new complex can then exit the epithelial cells to be carried to the liver.
Site of secretion
The intrinsic factor is secreted by the stomach. It is present in the gastric juice as well as in the gastric mucous membrane. The optimum pH for its action is 7 and it is inactivated at temperatures above 45 °C. It does not necessarily run parallel with the amount of HCl or pepsin in the gastric juice. So in some cases, the intrinsic factor may be present even if there is no HCl or pepsin or vice versa. The site of formation of the intrinsic factor varies in different species. In pigs it is obtained from the pylorus and beginning of the duodenum. In human beings it is present in the fundus and body of the stomach.
The limited amount of normal human gastric intrinsic factor limits normal efficient absorption of B12 to about 2 mcg per meal, a nominally adequate intake of B12. (Watanabe F. Vitamin B12 sources and bioavailability. Exp Biol Med (Maywood) 2007;232:1266–74. )
Clinical significance
In pernicious anemia, which is usually an autoimmune disease, autoantibodies directed against intrinsic factor or parietal cells themselves lead to an intrinsic factor deficiency, malabsorption of vitamin B12, and subsequent megaloblastic anemia. Atrophic gastritis can also cause intrinsic factor deficiency and anemia through damage to the parietal cells of the stomach wall. Pancreatic exocrine insufficiency can interfere with normal dissociation of vitamin B12 from its binding proteins in the small intestine, preventing its absorption via the intrinsic factor complex.
Other risk factors contributing to pernicious anemia are anything that damages or removes a portion of the stomach's parietal cells, including bariatric surgery, gastric tumors, gastric ulcers, and excessive consumption of alcohol.
Treatment
Patients experiencing an insufficiency in their intrinsic factor levels cannot benefit from a low dose oral vitamin B12 supplement, because it will not absorb through the wall of the small intestine. Historically, the disease was thought untreatable before the discovery that it could be managed with daily uptake of 300 g raw liver pulp (Nobel Prize in Physiology or Medicine 1934 to Whipple, Minot & Murphy). Unlike other water-soluble vitamins, vitamin B12 is stored in the liver. The high dose of vitamin B12 thus ingested allows enough of it to be taken up passively. As more and more potent liver extracts became available this repugnant treatment became unnecessary, improving the life quality of the patients. Today, synthetic vitamin B12 can be injected monthly, thus bypassing the digestive tract altogether.
Although IF is necessary for efficient absorption of B12, even without IF the intestines can directly absorb about 1% of ingested B12. Oral supplement of 500-1000 mcg (readily available OTC) per day provides adequate direct absorption without functioning IF. (Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, van Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005 May 23;165(10):1167-72. )
References
- ↑ Pocock, G and Richards, C (2006). Human Physiology:The Basis of Medicine (3rd ed.). Oxford University Press. p. 230. ISBN 978-019-856878-0.
- ↑ Hewitt JE, Gordon MM, Taggart RT, Mohandas TK, Alpers DH (June 1991). "Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11". Genomics 10 (2): 432–40. doi:10.1016/0888-7543(91)90329-D. PMID 2071148.
Further reading
- Howard TA, Misra DN, Grove M et al. (1996). "Human gastric intrinsic factor expression is not restricted to parietal cells". J. Anat. 189 (Pt 2): 303–13. PMC 1167747. PMID 8886952.
- Kozyraki R, Kristiansen M, Silahtaroglu A et al. (1998). "The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region". Blood 91 (10): 3593–600. PMID 9572993.
- Wahlstedt V, Gräsbeck R (1985). "Cobalamin-binding proteins in human urine: identification and quantitation". J. Lab. Clin. Med. 106 (4): 439–46. PMID 4045300.
- Remacha AF, Del RÃo E, Sardà MP et al. (2008). "Role of (Glu --> Arg, Q5R) mutation of the intrinsic factor in pernicious anemia and other causes of low vitamin B12". Ann. Hematol. 87 (7): 599–600. doi:10.1007/s00277-008-0465-0. PMID 18338170.
- Ament AE, Li Z, Sturm AC et al. (2009). "Juvenile cobalamin deficiency in individuals of African ancestry is caused by a founder mutation in the intrinsic factor gene GIF". Br. J. Haematol. 144 (4): 622–4. doi:10.1111/j.1365-2141.2008.07496.x. PMC 2636683. PMID 19036097.
- Mathews FS, Gordon MM, Chen Z et al. (2007). "Crystal structure of human intrinsic factor: cobalamin complex at 2.6-A resolution". Proc. Natl. Acad. Sci. U.S.A. 104 (44): 17311–6. doi:10.1073/pnas.0703228104. PMC 2077253. PMID 17954916.
- Fedosov SN, Fedosova NU, Berglund L et al. (2005). "Composite organization of the cobalamin binding and cubilin recognition sites of intrinsic factor". Biochemistry 44 (9): 3604–14. doi:10.1021/bi047936v. PMID 15736970.
- Gerhard DS, Wagner L, Feingold EA et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Tanner SM, Li Z, Perko JD et al. (2005). "Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene". Proc. Natl. Acad. Sci. U.S.A. 102 (11): 4130–3. doi:10.1073/pnas.0500517102. PMC 554821. PMID 15738392.
- Yassin F, Rothenberg SP, Rao S et al. (2004). "Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency". Blood 103 (4): 1515–7. doi:10.1182/blood-2003-07-2239. PMID 14576042.
- Gordon MM, Brada N, Remacha A et al. (2004). "A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency". Hum. Mutat. 23 (1): 85–91. doi:10.1002/humu.10297. PMID 14695536.
- Strausberg RL, Feingold EA, Grouse LH et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Andersen CB, Madsen M, Storm T et al. (2010). "Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes". Nature 464 (7287): 445–8. doi:10.1038/nature08874. PMID 20237569.
- Katz M, Lee SK, Cooper BA (1972). "Vitamin B 12 malabsorption due to a biologically inert intrinsic factor". N. Engl. J. Med. 287 (9): 425–9. doi:10.1056/NEJM197208312870902. PMID 5044916.
- Yazaki Y, Chow G, Mattie M (November 2006). "A single-center, double-blinded, randomized controlled study to evaluate the relative efficacy of sublingual and oral vitamin B-complex administration in reducing total serum homocysteine levels". J Altern Complement Med 12 (9): 881–5. doi:10.1089/acm.2006.12.881. PMID 17109579.
External links
- Intrinsic factor at the US National Library of Medicine Medical Subject Headings (MeSH)
- MedlinePlus Encyclopedia 002381
- Overview at colostate.edu
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