Vitamin B12

Anti-pernicious anemia factor, animal protein factor, factor x, Zoopherin

B-vitamins Active in Single Carbon Metabolism
Vitamins POSC/NUTR 645

Vitamin B12, History

1822, J.S. Combe describes pernicious anemia, and fatal disease and suggests it is related to a disorder of the digestive tract 1926, Minot & Murphy show that large amounts of liver cure the always fatal pernicious anemia

Vitamin B12

Vitamin B12, History 1928, W.B. Castle postulates some disorder of the digestive and assimilative organs extrinsic factor intrinsic factor Bases claim on curative power of beef muscle mixed with gastric juice Treatment = regurgitated beef

Vitamin B12

Vitamin B12, History

Castles work develops new concepts 6 fundamental mechanisms cause all deficiencies of Vitamin B12 & other vitamins 3 Inadequacies Ingestion, Absorption, or Utilization 3 Increases Requirement, Excretion, or Destruction

Vitamin B12

Vitamin B12, History

1934, Whipple, Minot & Murphy win Nobel prize for liver pernicious anemia therapy Whipple showed hemoglobin response in dogs (Fe effect) 1944 - 1950, Norris & Combs, Bird et al., Cary, the Zuckers, & Stokstad Find factors in fish meal, manure & liver Forms are ultimately shown to be identical Stokstad proves microbes make manure form

Vitamin B12

Vitamin B12, History

1948, Vitamin B12 isolated Dr. Karl Folkers, Merck-US, greatly aided by Dr. Mary Shorb who had a microbiological assay use as a screening tool Dr. E. Lester Smith, Glaxo Labs- UK, used relapsed pernicious anemics for assays. Identifies Co as constituent & uses as trace for purification by partition chromatography

Vitamin B12

Vitamin B12, History 1955, Structure elucidated. Dr. Dorothy Hodgkin in a series of Nature papers

Vitamin B12

Vitamin B12, Chemistry & Structure

Dark red crystalline solid Water soluble to 1% solution, soluble in ethanol Stable in aqueous solution between pH 4-7 @ R.T. Unstable at pH 2, rapidly destroyed at pH 9 CN form more stable than others Unstable with oxidizing or reducing agents Combines with many proteins UV light slowly destroys activity Optically active

Vitamin B12

Bioavailability & Absorption

1. Strong acid in stomach releases Vitamin B12 from food proteins
IF Acid pH

B12

2. Intrinsic Factor & acid secreted by the parietal cells

IF R B12 IF B12

IF R + B12 Pancreas

IF + B12

Ileal Receptor TCII-B12 IF

Vitamin B12

3. Liberated Vit B12 binds to R proteins

IF-B12

Bioavailability & Absorption

4. Pancreatic Proteases Degradation of R proteins
Acid pH

IF R

B12

5. Vitamin B12 & intrinsic factor combine

IF R B12 IF B12

IF R + B12 Pancreas

12

Ileal Receptor IF

12

Vitamin B12

6. Calcium ions IF + B stabilize B12/IF complex & promote receptor binding TCII-B

IF-B12

Bioavailability & Absorption

Vitamin B12

Biochemical Functions

Vitamin B12

Vitamin B12 participates in 3 known reactions: Methionine synthesis from homocysteine - methyl cobalamin MethylmalonylCoA Mutase - 5 adenosylcobalamin Leucine Mutase - 5 adenosylcobalamin

Biochemical Functions
1, 2-shift COOH COOH * CH2 CH2 COSCoA

H3C-C-H
COSCoA

L-Methylmalonyl CoA
Note:

Succinyl CoA
racemase
Vitamin B12

Cocarboxylase, CO2 ATP Mg++ Biotin Propinyl CoA

D-Methylmalonyl CoA

Vitamin B-12, Bioavailability/Absorption

Vitamin B12

Deficiency Signs
Failure to maintain rapidly turning over tissues Megaloblastic Anemia
Primative Erythroblast Proerythroblast Basophillic Normoblast
Note condensed Chromatin Blocked in Folate or B12 deficiency

Erythrocytes

Vitamin B12

Loose chromatin indicative of active cellular replication

Deficiency Causes
Primary Nutritional Vegetarian Diets Secondary Failure to make intrinsic factor Achlorhydria Pancreatic insufficiency proteases/R proteins

Vitamin B12

Deficiency Causes
Secondary Intestinal dysfunction Parasites Xenobiotics Sprue Nitrous Oxide exposure Congential Disorders

Vitamin B12

Deficiency Signs
Homocysteinemia Methylmalonic acidemia Loading test differential diagnosis Neurologic disease demyelination
Vitamin B12