Vitamin B12: Chemistry, Sources, Absorption, and Functions

3. Vitamin B12 [C61-64H84-90N14O13-14P ] Co.

4. Vitamin B12

5. CHEMISTRY • Vitamin B12 includes a group of cobalt, containing compounds known as cobalamins. The major forms found in plasma and tissue include • Methyl cobalamin Circulatory form • Deoxyadenocyl cobalmin ( storage Form) and • Hydroxy and cynaocobalamin(Supplemental form) All of these forms are biologically active.

6. R= CN,CH3,OH, Deoxyadenosyl Dimethylbenzimidazol

7. Food sources • Vitamin B12 occurs only in animal sources. The richest sources include • Lamb and calf beef • Kidney • Liver and • Brain.

8. Vitamin B12 Sources • Eggs, shellfish and dairy products. • Normal mixed diet contains 5-30 μg /day. • Vitamin B12 is heat stable and little is lost during cooking.

9. Daily Requirement • Infants = 0.3 ug/day • Children = 1-2 ug/day • Normal Adults = 3 ug/day • In Pregnancy / Lactation = 4 ug/day

10. Recommended Dietary Allowances • 3.0 g of Vitamin B12 for adults allows for maintenance of adequate nutrition and substantial reserve body pool.

11. Excretion • The vitamin is lost mainly in urine and feces. • Typical daily losses of vitamin B12 are between 1- 4 μg. • The daily requirement matches daily losses.

12. In Food • Vit B12 is attached to protein in deoxyadenosyl form. • To be utilized it is released by acid hydrolysis in the stomach or trypsin digestion in intestine. • Then it combines with the Intrinsic Factor (IF), a protein secreted by the stomach which acts as carrier to ileum for absorption.

13. Vitamin B12 absorption • VitaminB12 absorption is an active process, which occurs in the ileum. • Vitamin B12 is liberated from food by gastric and duodenal enzymes and complexes in a 1:1 ratio with the intrinsic factor. • IF is a glycoproein, MW 45,000, which is synthesized and secreted by gastric parietal cells.

14. Vitamin B12 Stores • Normal body stores of vitamin B12 is about 3 - 4 mg. • Primarily in liver. • This would be sufficient for 3 years if dietary intake ceased or if the ability to absorb the vitamin was lost. 

15. FATE OF IF-B12 COMPLEX • IF: B12 complex then progresses to the ileum where it attaches to specific receptors on the ileal mucosal cells. • This process requires the presence of calcium ions and neutral pH. • The vitamin is internalized from the complex and • Released into the portal circulation after 6 hours. 

16. Vitamin B12 Transport • There are three vitamin B12 transport proteins normally present in the plasma, which are known as Transcobalamines (TCI-TCII-TCIII). • The physiologically active is TCII which complex in a 1:1 ratio with vitamin B12. • The complex then binds to specific surface receptors on developing blood cells in the bone marrow. • Finally Vitamin B12 is released by hydrolysis.

17. The plasma half-life of TCII is 12 hours and congenital absence of it causes megaloblastic anemia . • Transcobalamines I and III are -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. 

18. Cbl R Stomach R-Cbl R-Cbl IF R TCII Cbl TCI-Cbl IF-Cbl Duodenum Cbl IF TCII-Cbl TCII-Cbl TCII IF-Cbl IF-Cbl Terminal Ileum GI ABSORPTION OF COBALAMIN

20. COBALAMIN REACTIONS Methylmalonyl CoA Homocysteine Methionine MethylCobalamin AdenosylCobalamin THF NH NH CH3 Succinyl CoA

21. Vitamin B12 Stores • Normal body stores of vitamin B12 about 3-4 mg, primarily in liver. This would be sufficient for 3 years if dietary intake ceased or if the ability to absorb the vitamin was lost. 

22. IMPORTANT FUNCTIONS • Vitamin B12 is required by all cells of the body, especially • Gastro-intestinal tract • Bone marrow and • Nervous system. • Within bone marrow, it is involved in conversion of ribose nucleotides into deoxyribose nucleotides

23. IMPORTANT FUNCTIONS • The most well-known function of B12 is its role in the development of red blood cells. • As red blood cells mature, they require genetic information provided by DNA. • Without B12, synthesis of DNA becomes defective, and so does the information needed for RBCs formation.

24. As a result • The cells become oversized and poorly shaped, begin to function ineffectively and a condition called pernicious anemia develops. • Sometimes pernicious anemia isn't caused by a lack of B-12 itself, but by a lack of intrinsic factor, (protein) required for the absorption of B-12. • Bonemarrow cannot produced mature red blood cells and so releases the large, immature precursor (macrocytes) into circulation.

25. Other roles for vitamin B12 • Protein in food required for growth and repair of cells depends upon B-12 for proper cycling through the body. • Many of protein's key components( amino acids) become unavailable for use in the absence of B12.

26. FUNCTIONS • B12 participates in two important chemical reactions in human body. • Metioninesynthasecatalysed conversion of homocystein to methionine. 2. The 5-deoxyadenosyl derivatives of B12 is required for methyl malonyl-CoAmutasewhich converts methylmalonylCoA to succinylcoA.

27. COBALAMIN REACTIONS Methylmalonyl CoA Homocysteine Methionine MethylCobalamin AdenosylCobalamin THF NH NH CH3 Succinyl CoA

28. Contd: • This is a key reaction in the catobolism of Valine, isoleucine,methionine,threonine, odd chain fatty acids, thymine and side chain of cholesterol. • As expected B12 deficiency causes accumulation of both homocystein and methylmalonic acid.

29. B-12 deficiency ,if present • Will cause Megaloblastic anemia. • Is due to the effect of B12 on folate metabolism. • Methionine synthesis • Homocysteine + N5 methyl THF → Methionine + THF • Is the only pathway by which N5 – methyl THF can return to the tetrahydrofolate pool. • Thus, in B12 deficiency essentially all of the folate becomes “trapped” as the N5 methyl derivative, causing a build up of N5 – methyltetrahydrofolate

30. Mechanism of Megaloblastic Anemia • Vitamin B12 deficiency leads to Deficiency of THF. • Deficient synthesis of Purines and pyrimidines. • Deficient synthesis of DNA • Inability of RBCs to get mature in bone marrow. • Immature megaloblasts are released in to circulation. • Megaloblast are not efficient in O2 delivery. • Leads to megaloblasic anemia.

31. Symptoms of megalotblastic anemia • The symptoms of megaloblastic anemia include : • Pallor • Weight loss • Anorexia • Glossitis • Sprue, and in advanced stages • Degeneration of spinal cord.

32. Other roles for vitamin B12 A steps in CHO and fat metabolism requires B12 for its completion, deficiency of the vitamin can affect the metabolism of CHO and fats in the body.

33. Toxic Effect • No toxic effect in humans

34. THANKS

35. Introduction • Pernicious anemia, a megaloblastic anemia associated with neurological deterioration caused by progressive demylelination of nervous tissue. • Was fatal till 1926. • Then liver extract showed to be curative. • subsequent work showed that liver contains an extrinsic factor in the form of Vit. B-12. • Intrinsic factor is also required which is produced by the body, which helps in its absorption.

36. Recent studies have shown that B12 deficiency is associated with increased expression of tumor necrosis factor α (TNF- α) and nerve growth factor (NGF) and decreased expression of epidermal growth factor (EGF) and interleukin in cerebrospinal fluid (CSF), but the mechanism of these changes and their effect on neural function remain unknown.