Vitamin B12

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Vitamin B12

• Julie Roche
• 12/7/04

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Vitamin B12


                                                                             


                                                                                         

• Cobalamin
• Porphyrin ring
• Cobalt
• Nucleotide
• Net charge 1

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Vitamin B12 Derivatives

• Cyanocobalamin (digested form)
• Hydroxycobalamin
• Chlorocobalamin
• Methylcobalamin
• Adenosylcobalamin
• (5-deoxyadenosylcobalamin)

physiological useful forms
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Biosynthesis of Vitamin B12

• One of the most complicated biosynthetic pathways
• Involves over 30 enzymes
• Two pathways
• Aerobic
• anaerobic
• 16 intermediates between uroporphyrinogen III and
  adenosylcobalamin (aerobic pathway)

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Difference between pathways

• Need for molecular O2
• Aerobic between precorrin-3a and b
• Point of Cobalt addition
• Anaerobic added early, between uroporphyrinogen
  III and precorrin-2
• Aerobic added late, between hydrogenobyrinic
  acid a,c-diamide and cob(II)lyrinic acid
  a,c-diamide

Anaerobic synthesis is more difficult
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Developments Leading to the Discovery of the
Biosynthetic Pathway of Vitamin B12
                                                
                        

• 13C labeling (1990)
• NMR spectroscopy

• Enzymology
• Molecular genetics

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Vitamin B12

• Produced on an industrial level
• Fermentation
• Methanosarcina
• Butribacterium
• Acetobacterium
• Propionibacterium
• Produces largest amt of cobalamin
• Secretes propionic acetic acid
• Propionic acid inhibits cobalamin production

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Vitamin B12 affects two Major Pathways

• Homocysteine
• Methionine

• Methylmalonyl CoA
• Succinyl CoA

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The effects of Vitamin B12 on the conversion of
homocysteine to methionine

Homocysteine
Methionine Synthase
Methylcobalamin
Methionine
5-methyltetrahydrofolate
tetrahydrofolate
Tetrahydrofolate methyltransferase
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The effects of Vitamin B12 on the conversion of
Methylmalonyl CoA to Succinyl CoA

Methylmalonyl Co A
Methylmalonyl CoA mutase
Adenosylcobalamin
Succinyl CoA
Kreb's cycle
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Vitamin B12 Deficiency

• homocysteine and methylmalonyl CoA
• Increase in methylmalonyl CoA
• Increased enzyme activity in fatty acid synthesis
• Build up of odd fatty acids around peripheral
  nerves
• Increase in homocysteine
• Vascular/nervous problems

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Vitamin B12 Deficiency

• Excess homocysteine MMA excreted in urine
• Diagnosis for cobalamin deficiency
• Methylmalonyl CoA mutase Methionine synthase
  affect amino acid metabolism
• Amino acid metabolism inhibited by deficiency

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Vitamin B12 Binding Proteins

Transcobalamin I
Transcobalamin II
Transcobalamin III
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Transcobalamin I

• R-type binding protein
• 33 is carbohydrate
• Molecular weight 125,000-150,000
• Beta globulin
• Contains more sialic acid than transcobalamin III
• Carries 80 of Vitamin B12 in blood
• Vitamin B12 has half-life of 10-12 days when
  bound to it

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Transcobalamin II

• Molecular weight 38,000
• Alpha globulin
• NOT a glycoprotein
• Carries less than 25 of Vitamin B12 in blood
• Vitamin B12 has half-life of under 1 ½ hours when
  bound to it
• Encourages absorption in a number of tissues
• Degenerates once B12 is released
• B12 then recirculates
• Transcobalamin II deficiency results in
  pernicious anemia

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Transcobalamin III

• R-type binding protein
• 33 is carbohydrate
• Molecular weight 125,000-150,000
• Alpha globulin
• Released from granulocytes
• Contains more fucose than transcobalamin I

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Antibacterial Roles of Transcobalamin I III

• Binds to large amounts of vitamin B12 and carries
  it to liver
• Excreted in bile
• Prevents bacteria from using the vitamin for
  growth

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Vitamin B12 separated from Foods in stomach
Binds to Transcobalamin I and III
Binds to receptors on Liver cells
Pinocytosis
Binding Proteins Degraded Within 1 ½ hrs
20 excreted in bile
Cobalamin
80 binds to BP reenters blood
Carried to Ileum and absorbed in by endocytosis
BP degenerates, IF binds to cobalamin
Returns to liver or Carried to other tissues
Released and bound to Transcobalamin II
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Sources of Vitamin B12

• Fish
• Eggs
• Meat
• Dairy Products

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Vitamin B12 deficiency

• Cobalamin level in blood below 200 pg/ mL
• Common in elderly

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Causes of Vitamin B12 Deficiency
Most Common

• Malabsorption (inability to absorb food
  containing cobalamin)
• Inability to separate cobalamin from food in
  stomach
• Lack of recommended intake
• Inability to use/store cobalamin
• Proton pump inhibitors
• Gastritis
• Stomach/bowel resection
• Chrons disease
• Pancreatitis
• Gastric lymphoma
• Myeloma
• HIV
• Antibiotics
• Anticonvulsants
• Excess Vitamin C
• Nitric Oxide

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Symptoms/Effects of Vitamin B12 Deficiency

• Pernicious Anemia (Vitamin B12 is necessary for
  RBC production)
• Lethargy
• Weight loss
• Weakness
• Dementia
• Leucopenia
• Thrombocytopenia
• Axonal degeneration
• Demyelination
• Urethral Sphincter problems
• Depression
• Alzheimers Disease
• Increased liver weight
• Fat accumulation around heart, liver, peripheral
  nerves

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Symptoms/Effects of Vitamin B12 Deficiency

• Increase
• Homocysteine
• MMA
• Bilirubin excretion
• LDH
• Liver glycogen
• Mitochondrial cristae in liver
• Hepatic citrate synthase
• Propionic acid
• Succinate dehydrogenase
• Cytochrome c activity
• Propionyl CoA
• Amino Acids
• Cell metabolism
• Protein synthesis
• Fatty acid synthesis enzymes
• ATP citrate lyase
• Causes rise in Krebs cycle

• Decrease
• Transcobalamin II
• Intrinsic factor

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Treatment

• Supplements
• Oral pills
• Intramuscular
• Intranasal
• Sublingual

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500-2000
3-7 days... monthly... 4x year