Vitamin b12
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Presentation given by Dr. Karthikeyan at Department of Biochemistry, Maulana Azad Medical College, NewDelhi.
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Vitamin b12
- 1. Vitamin B12 Moderator: Dr. B.C. Koner
- 2. Facts • Only water soluble vitamin that is stored • Synthesized exclusively by microbes • Dietary source is exclusively of animal origin • Rare compound with direct metal-carbon bond
- 3. Structure
- 5. Different forms • Cyano • Methyl • Adenosyl • Hydroxo • Aquo
- 6. Smokers should note that the cyanide absorbed from the smoke into the blood causes the replacement of the 5'- deoxyadenosyl group by a cyanide.
- 7. Dietary source • Present only in foods of animal origin • That too is a product of microbial synthesis. • Plants do not use B12.
- 8. Iran study fruit fertiliser
- 10. Absorption • Peptic digestion releases dietary vitamin B12, which then binds to salivary B12-binding proteins called Haptocorrins, or R binders. • R-B12 complexes are transported to the duodenum and processed by pancreatic proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal cells of the gastric fundic mucosa. • The intrinsic factor-B12 complex passes to the distal ileum and attaches to the epithelial intrinsic factor receptors, which leads to absorption of vitamin B12. • The absorbed B12 is bound to transport proteins called transcobalamins, which then deliver it to the liver and other cells of the body.
- 11. Haptocorrin • R-binder/cobalophilins/Transcobalamin-I • encoded by the TCN1 gene • produced by the salivary glands and the parietal cells in the stomach. • Function: Protection of the acid-sensitive vitamin B12 while it moves through the stomach. • Enterohepatic circulation
- 12. Intrinsic Factor of castle • Glycoprotein secreted by parietal cell of stomach in the region of fundus and body • optimum pH for action – 7 • Secretion of IF is stimulated by food, histamine and gastrin; inhibited by vagal block. • After digestion of haptocorrin by pancreatic enzymes, binds to B12 in small intestine in 1:1 ratio. • Complex itself is endocytosed by IF receptors in ileum
- 13. Cubam • Cubam, is the multi-ligand receptor located in the terminal ileum, specializing in absorption of vitamin B12. • Cubam is made up of amnionless (AMN), and cubilin • Cubilin is the receptor, whereas amnionless is involved in the receptor mediated endocytosis of the complex.
- 14. No transmembrane domain in cubilin
- 15. Transcobalamines TCII: • The physiologically active form is TCII , a beta globulin synthesized mainly by liver • 1:1 ratio • The complex then binds to specific surface receptors on developing blood cells in the bone marrow. Vitamin B12 is then released by hydrolysis. The TCII is not reutilized. • The plasma half-life of TCII is 12 hours and congenital absence of it causes megaloblastic anaemia within weeks of birth. TC I and III (cobalophillins): • -globulins synthesized by granulocytes and known as R-binders that are found in a wide range of body fluids. TCI&III do not readily release vitamin B12 to the developing tissues. • The plasma half-life is 9-12 days and congenital absence of them causes no physiological impairment. It is postulated that cobalophillins aid in host defencse against bacteria by depriving them of B12.
- 17. B12-Dependent Enzymes • Methylmalonyl CoA mutase (adenosyl cobalamin) • Methionine synthase (methyl cobalamin) • Leucine aminomutase
- 22. Folate trap
Editor's Notes
- Difference: 1. Cobalamin contains a corrin ring system that differs from the porphyrins in that two of the pyrrole rings are linked directly rather than through a methene bridge. 2. it is not planar
- Cyanocobalamin form of B12 does not occur in nature normally By-product of the fact that other forms of B12 are avid binders of cyanide (-CN) which they pick up in the process of activated charcoal purification of the vitamin after it is made by bacteria in the commercial process. easy to crystallize and is not sensitive to air-oxidation, it is typically used as a form of B12 for food additives and in many common multivitamins. Pure cyanocobalamin possesses the deep pink color associated with most octahedral cobalt(II) complexes and the crystals are well formed and easily grown up to millimeter size.
- Megalin is a cell-surface receptor/transporter consisting of a large extracellular region, a single transmembrane domain, and a C-terminal cytoplasmic tail. The extracellular domain of megalin contains four clusters of lipoprotein receptor ligand-binding repeats (blue), growth factor repeats, an EGF repeat, and YWTDspacer regions. The second cluster of ligand-binding repeats has been identified as a common binding site for several ligands including apolipoprotein E (Apo E), apolipoprotein M (Apo M), retinol binding protein (Rbp), and transthyretin (Ttr). Megalin also binds the soluble form of the folate receptor (Folr1), and the morphogen sonic hedgehog (Shh). The cytoplasmic tail of megalin binds Dab2, a cytosolic adapter protein important for megalin-mediated endocytosis, and Dab2 binds and recruits Myo6 to clathrin-coated vesicles. The receptor-associated protein (Lrpap1; RAP) binds both megalin and cubilin. Cubilin is a peripheral membrane receptor comprised of a short amino terminal, eight EGF type domains, and 27 CUB domains (green). The amino-terminal end of cubilin is attached to the extracellular part of amnionless (Amn), and amnionless provides the transmembrane domain necessary for the anchoring and endocytic trafficking of cubilin. Cubilin ligands include transferring (Trf), albumin, hemoglobin, apolipoprotein A1 (ApoA1), and intrinsic factor (IF)-vitamin B12. Why it is known as amnionless – defect is associated with amnionless gastrulation in rodents
- Hepatocytes take up Cbl or its analogues (CblAs) bound to HC via the asialoglycoprotein receptor (ASGP-R) and Cbl bound to TC II via TC II-R. Cbl liberated following degradation of HC–Cbl or TC II–Cbl is either stored in the form of Cbl-dependent enzymes or secreted via bile to be reabsorbed. CblA either released from HC or still bound to it is secreted via bile. HC in the bile might originate from the circulation (via uptake by the hepatocytes) or from de novo synthesis by the liver. In either case it is degraded in the intestinal lumen by pancreatic proteases. Once in the lumen, the secreted Cbl and CblA bind to gastric IF and, depending upon the availability of free IF–Cbl binding sites of cubilin, are either reabsorbed as a part of the enterohepatic circulation or excreted in the faeces. The three receptors are shown in their monomeric forms, although cubilin and TC II-R are known to exist as a trimer and dimer, respectively; only one of the two subunits of ASGP-R is shown