Vitamin B12

Structure
Functions
Sources
Metabolism
Requirements
Deficiency
Toxicity

I.  Structure

1. Vitamin B₁₂ is a generic term for a group of compounds called corrinoids because of their corrin nucleus
2. Corrin is a macrocyclic ring of four reduced pyrrole rings linked together with Co at its center to which is attached a nucleotide, 5, 6-dimethylbenzimidazole. (Figure 9.33)
3. Also attached is one of the following:
   1. CN..............................Cyanocobalamin
   2. OH..............................Hydroxocobalamin
   3. H₂0.............................Aquocobalamin
   4. NO₂............................Nitrocobalamin
   5. 5'- deoxyadenosyl......5'- deoxyadenosylcobalamin
   6. CH₃............................Methylcobalamin
4. Only 5'- deoxyadenosylcobalamin and methylcobalamin are active as coenzymes

II.  Functions

1. Conversion of homocysteine into methionine
   1. Requires methylcobalamin
   2. Necessary for converting inactive methyl folate to the active form, THF
      1. Cobalamin, bound to homocysteine methyl transferase apoenzyme, picks up CH₃ group from N⁵ methyl THF and transfers it to homocysteine
      2. Methionine and free THF are produced
      3. THF can then be converted into any of its coenzyme forms
      4. This reaction largely explains the synergism between folate and vitamin B₁₂
2. Conversion of methylmalonyl CoA a metabolite of propionyl CoA to succinyl CoA, the Krebs cycle intermediate
   1. This reaction is inhibited in cobalt deficient ruminants.
   2. Reaction requires adenosylcolbalamin for methylmalonyl CoA mutase
   3. When vitamin B₁₂ is deficient, mutase activity is impaired and methylmalonic acid accumulates in body fluids
3. Isomerization of L-leucine and beta-leucine
   1. The enzyme leucine aminomutase requires adenosylcobalamin
   2. Beta-leucine generated by intestinal bacteria may be converted to L-leucine within the body
   3. L-leucine may be converted to beta leucine which can be transaminated in a vitamin B₆ (PLP) -dependent reaction and provide an alternative pathway for leucine catabolism

III.  Sources

1. All naturally occurring vitamin B₁₂ is produced by microorganisms
2. Dietary sources for humans are animal products which derived their cobalamins from microorganisms
3. Any vitamin B₁₂ in plant foods could probably be traced to microorganisms
   1. Contamination with manure
   2. Presence of nitrogen fixing bacteria in legume root nodules
   3. Contaminated hands taking food to mouth
4. Food sources of cobalamins
   1. Adenosyl - and hydroxocobalamin
      1. Meat and meat products
      2. Poultry, fish, shellfish (clams, oysters)
      3. Eggs (especially yolk)
   2. Methyl and hydroxocobalamin
      1. Milk and milk products (cheese, yogurt)
   3. Cyonocobalaman
      1. Tobacco
      2. Commercially available vitamins (along with hydroxocobalamin)
      3. Within the body, cyonocobalamin is converted to aquo- or hydrocobalamin

IV.  Metabolism

1. Absorption and transport
   1. Ingested cobalamins are released from polypeptides in foods by the gastric proteolytic enzyme pepsin
   2. Once released from foods, vitamin B₁₂ absorption involves 2 proteins
      1. Intrinsic factor (IF), a glycoprotein synthesized by gastric parietal cells
      2. R proteins which have a high affinity for cobalamins are found in body fluids
   3. Free cobalamin complexes with R protein
      1. Complex moves into the small intestine
      2. Pancreatic proteases in the duodenum hydrolyze R protein and release cobalamin
      3. R proteins may protect vitamin B₁₂
   4. In the proximal small intestine, IF binds cobalamin released from R protein
      1. Cobalamin-IF complex travels to ileum where receptor sites for vitamin B₁₂ are present
      2. Peak levels in blood not reached before 8-12 hr after ingestion
      3. With pharmacologic doses of vitamin B₁₂, passive diffusion accounts for much of the absorption (thus effectiveness of high vitamin B₁₂ levels in treatment of pernicious anemia)
      4. Much of cobalamin in bile and other intestinal secretions can be reabsorbed
      5. Following absorption, cobalamins bind to transcobalamins (TC) which carry them to tissues
      6. TCII also assists uptake of cobalamin by tissues which have receptors for TCII
      7. Cobalamins with TC are taken up by endocytosis
      8. Within the lysosome, TCII is degraded and hydroxycobalamin is released
      9. Hydroxycobalamin is converted to the active coenzyme forms, methylcobalamin and adenosylcobalamin
      10. Vitamin B₁₂ is stored in the liver for up to years (other water soluble vitamins are not stored)
2. Excretion
   1. Most of cobalamin excretion occurs in feces via bile but 65-75% of that secreted into the gastrointestinal tract is reabsorbed.
   2. Little urinary excretion occurs.
   3. Whole body turnover of vitamin B₁₂ is approximately 0.1% per day.

V.  Requirements

1. Recommended allowances
   1. Human = 2 micrograms per day
   2. Poultry = 2-4 micrograms per pound of diet
   3. Swine = 5-10 micrograms per pound of diet
2. Factors increasing requirement
   1. Vitamin C in doses of 500 mg or more with meals or up to 1 hr after a meal may diminish vitamin B₁₂ availability or destroy it
   2. Pancreatic insufficiency could interfere with release of cobalamin from R protein
   3. Deficiency of intrinsic factor (pernicious anemia)

VI.  Deficiency

1. Human- pernicious anemia
   1. Macrocytic anemia
   2. Megaloblastic bone marrow
   3. 3Achlorohydria
   4. Glossitis
   5. Neurological manifestations
      1. Peripherial neuritis
      2. Degenerative lesions of spinal cord
      3. Paresthesia (abnormal skin sensation)
2. Chicks
   1. No anemia
   2. Reduced growth
   3. Reduced hatchability
   4. Chicks from deficient eggs have muscle and leg abnormalities (perosis)
3. Swine
   1. No anemia
   2. Reduced growth, rough hair coat, dermatitis
   3. Nervous and irritable
4. Sheep and cattle
   1. B₁₂ normally synthesized in rumen
   2. Lack of cobalt
      1. Anemia
      2. Loss of appetite
      3. Emaciation
      4. Urinary excretion of methylmalonic acid

VII.  Toxicity

1. No clear toxicity from massive doses of vitamin B₁₂ has been reported

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