Vitamin B12 (Cobalamin) lecture slides notes
- 1. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences COBALAMIN (VITAMIN B12)
- 2. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Inroduction: • Synonyms are cobalamin, extrinsic factor (EF) of Castle and antipernicious anemia factor. • In 1849, Thomas Addison described pernicious anemia. • William Murphy and George Minot showed that liver therapy is very effective to treat pernicious anemia (Nobel prize, 1934). • Dorothy Hodgkin suggested the structure by X-ray diffraction studies (Nobel Prize, 1964). • Later Robert Woodward synthesized B12 and proved the structure (Nobel prize, 1965).
- 3. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Chemistry Of Vitamin B12: • Vitamin B12 is the only vitamin with a complex structure. • The structure of vitamin B12 consists of a corrin ring with a central cobalt atom. • Four pyrrole rings coordinated with a cobalt atom is called a Corrin ring. • The 5th valency of the cobalt is covalently linked to a substituted benzimidazole ring. This is then called cobalamin. • The 6th valency of the cobalt is satisfied by any of the following groups: cyanide, hydroxyl, adenosyl or methyl.
- 4. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences
- 5. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences
- 6. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Different forms of vitamin B12 1. Cyanocobalamin • When cyanide is added at the R position, the molecule is called cyanocobalamin. • During the isolation procedure, cyanide is added to get stable crystals. • The CN group has no physiological function, it is only a laboratory artefact. • Oral preparations are in this form. 2. Hydroxy Cobalamin • When hydroxyl group is attached at the R position, it is called hydroxy cobalamin or vitamin B12a. • Injectable preparations are in this form.
- 7. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences 3. Adenosyl Cobalamin • When taken up by the cells, these groups are removed and deoxy adenosyl cobalamin or Ado-B12 is formed. • This is the major storage form, seen in liver. • When the methyl group replaces adenosyl group, it is known as methyl cobalamin. • This is the major form seen in blood circulation as well as in cytoplasm of cells. • The Ado-B12 and methyl B12 are the functional co-enzymes in the body. 4. Methyl Cobalamin
- 8. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Absorption of Vitamin B12: • Absorption of vitamin B12 requires two binding proteins. First is the intrinsic factor (IF) of Castle. Intrinsic factor is secreted by the gastric parietal cells. It is a glycoprotein. • The second factor is cobalophilin, secreted in the saliva. • Gastric pepsin release the vitamin from proteins of the food, and then B12 binds with cobalophilin. • In duodenum, cobalophilin is hydrolyzed by trypsin of pancreatic juice; vitamin is released, and then vitamin binds to intrinsic factor. • In pancreatic insufficiency (absence of trypsin), the vitamin may not be released. Then vitamin-cobalophilin complex is excreted, resulting in vitamin deficiency.
- 9. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences (A) =Intrinsic factor secreted from stomach reaches intestine; (B) = Vitamin B12 absorbed with the help of intrinsic factor;
- 10. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences • One molecule of IF can combine with two molecules of B12. • This IF-B12 complex is attached with specific receptors on mucosal cells (mediated by Ca2+ ions). The whole IF-B12 complex is internalized. • It may be noted that B12 is absorbed from ileum, while folic acid is from jejunum. Transport and Storage • In the blood, methyl B12 form is predominant. Transcobalamin, a glycoprotein, is the specific carrier. Physiologically Transcobalamine II is more important. • It is stored in the liver cells, as ado-B12 form, in combination with transcorrin. Generally, B complex vitamins are not stored in the body, B12 is an exception. • Whole liver contains about 2 mg of B12, which is sufficient for the requirement for 2–3 years.
- 11. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Functional Role of B12 Methyl Malonyl CoA Isomerase: • L-Methyl malonyl CoA is isomerized by methylmalonyl CoA mutase (containing Ado-B12) to succinyl CoA, which enters into citric acid cycle. • In B12 deficiency, methylmalonyl CoA accumulates and methyl malonic aciduria occurs. • The metabolism of odd chain fatty acids, valine, isoleucine, methionine and threonine leads to the production of methylmalonyl CoA.
- 12. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Homocysteine Methyl Transferase: • Step 2 in Figure is catalyzed by the enzyme methionine synthase or homocysteine methyl transferase. • The steps marked as 1 and 2 in Figure need the activity of vitamin B12 (methyl cobalamin). Methyl Folate Trap and Folate Deficiency: • The production of methyl THFA is an irreversible step. Therefore, the only way for regeneration of free THFA is step No. 1 in Figure. • When B12 is deficient, this reaction cannot take place. This is called the methyl folate trap. This leads to the associated folic acid scarcity in B12 deficiency. • Thus folic acid deiecency can cause hyperhomocysteinemia and heart problems.
- 13. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Causes of B12 Deficiency Nutritional: • Nutritional vitamin B12 deficiency is very common among vegetarians of low socioeconomic group. • The only source for B12 in vegetarian diet is curd/milk, and lower income group may not be able to afford it. Decrease in Absorption: • Absorptive surface is reduced by gastrectomy, resection of ileum and malabsorption syndromes. Addisonian Pernicious Anemia: • It is an autoimmune disease in which antibodies are generated against IF. • So, IF becomes deficient, leading to defective absorption of B12. (C) = In pernicious anemia, antibody against IF is produced; (D) = In presence of antibody, absorption is not taking place
- 14. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Deficiency Manifestations 1. Folate trap: • Vitamin B12 deficiency causes simultaneous folate deficiency due to the folate trap. • Therefore all the manifestations of folate deficiency are also seen. 2. Megaloblastic anemia: • In the peripheral blood, megaloblasts and immature RBCs are observed. • The peripheral blood picture in folate deficiency is described as macrocytic, and in cobalamin deficiency as megaloblastic. In B12 deficiency, there are additional neurological symptoms. Macrocytic anemia THFA dificiency Megaloblastic anemia with nucleated RBCs in vitamin B12 deficiency
- 15. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences 3. Abnormal homocysteine level: • In vitamin B12 deficiency, step No. 2 is blocked, so that homocysteine is accumulated, leading to homocystinuria. • Homocysteine level in blood is related with myocardial infarction. So, B12 and folic acid are protective against ischemic heart disease. 4. Demyelination: • In vitamin B12 deficiency, homocysteine levels are high and active methionine (methyl donor to various acceptors) is not formed. • Therefore methylation of phosphatidyl ethanolamine to phosphatidyl choline is not adequate. • This leads to deficient formation of myelin sheaths of nerves, demyelination and neurological lesions.
- 16. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Requirement of Vitamin B12 Normal daily requirement is 1–2 mg/day. During pregnancy and lactation, this is increased to 2 mg/day. Dietary Sources: • Vitamin B12 is not present in vegetables. • Liver is the richest source but also present in meat, fish and eggs. • Curd is a good source, because lactobacillus can synthesize B12. Products available in the market: Methecobal Cobalmin Bevidox Sangobion Nerobion
- 17. Abbottabad University Of Science And Technology Department Of Pharmaceutical Sciences Extra stuff