3. 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.

4. 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.

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

6. Vitamin B12

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

8. 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.

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

10. Daily vitamin B12 requirement
The only source available to man is dietary.
Additional dietary sources are eggs, shellfish and dairy products.
Normal mixed diet contains 5-30 μg /day.
Vitamin B12 is heat stable and little is lost
during cooking.

11. 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 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. 

14. 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.

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

19. Absorption and Metabolism
Vitamin B12 is absorbed through receptor sites in the ileum, mediated by intrinsic factor which is produced by glands in stomach.
Vitamin is then transported across the intestinal cell and then into blood stream.
Vitamin B12 is normally stored in liver for 3 to 5 years.

20. GI ABSORPTION OF COBALAMINIF R
Cbl
R-Cbl
IF-Cbl
TCII
TCII-Cbl
Stomach
Duodenum
Terminal Ileum
TCI-Cbl

21. COBALAMIN REACTIONS Methylmalonyl CoA Succinyl CoA Homocysteine
Methionine
Methyl Cobalamin
Adenosyl Cobalamin
THF
N H
N H
CH3
Succinyl CoA

23. COBALAMIN REACTIONS Methylmalonyl CoA Succinyl CoA Homocysteine
Methionine
Methyl Cobalamin
Adenosyl Cobalamin
THF
N H
N H
CH3
Succinyl CoA

24. 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. 

25. 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

26. 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.
Bone marrow cannot produced mature red blood cells and so releases the large, immature precursor (macrocytes) into circulation.

27. 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.

28. FUNCTIONS
B12 participates in two important chemical reactions in human body.
Metionine synthase catalysed conversion of homocystein to methionine.
2. The 5-deoxyadenosyl derivatives of B12 is required for methyl malonyl-CoA mutase which converts methylmalonyl CoA to succinyl coA.

29. 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.

30. B-12 deficiency ,if present
The 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

31. THF, if deficient
Tetrahydrofolate derivatives are needed for purine biosynthesis.
By replenishing the THF pool , large amounts of supplemental folate can overcome the megaloblastic anemia, but not the neurolagical problems.
This is the crux of the current debate on the optimal levels for folate fortication of foods.
It is the megaloblastic anemia that usually brings the patient into the doctor’s office.

32. Thus, by masking the anemia, routine fortification of foods with high levels of folate could prevent detection of B12 deficiency until the neurological damage had become irreversible.

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

34. It has been proposed that the demyelination associated with B12 deficiency is caused by methylmalonyl CoA accumulation in two ways.
(1) methylomalonyl CoA is a competitive inhibitor of malonly CoA in fatty acid biosynthesis. Because the myelin sheath is continually running over, any sever inhibition of fatty acid biosynthesis will lead to its degeneration.

35. (2) Methylmalonyl CoA can substitute for malonyl CoA in fatty acid synthesis leading to synthesis of branched-chain fatty acids, which may disrupt membrane structure.
However the neurologic symptoms of B12 deficiency cannot be fully explained by either mechanism, since accumulation of both methylmalonic acid and homocysteine is required for demyelination.

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.

37. Other roles for vitamin B12
Since 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.

38. Toxic Effect
No toxic effect in humans