Vitamin B12
Julie Roche
12/7/04
Vitamin B12
Cobalamin
Porphyrin ring
Cobalt
Nucleotide
Net charge = +1
Vitamin B12 Derivatives
Cyanocobalamin (digested form)
Hydroxycobalamin
Chlorocobalamin
Methylcobalamin
Adenosylcobalamin
(5’-deoxyadenosylcobalamin)
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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)
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
Developments Leading to the
Discovery of the Biosynthetic
Pathway of Vitamin B12
• 13C labeling (1990) • Enzymology
• NMR spectroscopy • Molecular genetics
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
Vitamin B12 affects
two Major Pathways
• Homocysteine • Methylmalonyl CoA
• Methionine • Succinyl CoA
The effects of Vitamin B12
on the conversion of
homocysteine to methionine
Homocysteine
Methionine Synthase
Methylcobalamin
Methionine
5-methyltetrahydrofolate tetrahydrofolate
Tetrahydrofolate methyltransferase
The effects of Vitamin B12
on the conversion of
Methylmalonyl CoA to Succinyl CoA
Methylmalonyl Co A
Methylmalonyl CoA mutase
Adenosylcobalamin
Succinyl CoA
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
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
Vitamin B12 Binding
Proteins
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
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
80
70
60
50
40
TC I
30 TC II
20
10
0
Amt of B12
Carried (%)
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
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
Vitamin B12 separated from Binds to Transcobalamin I
Foods in stomach 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
BP degenerates, IF binds to Carried to Ileum and absorbed
cobalamin in by endocytosis
Released and bound to Returns to liver or
Transcobalamin II Carried to other tissues
Sources of Vitamin B12
• Fish
• Eggs
• Meat
• Dairy Products
Vitamin B12 deficiency
Cobalamin level in blood = below 200
pg/ mL
Common in elderly
Causes of Vitamin B12
Deficiency
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
Chron’s disease
Pancreatitis
Gastric lymphoma
Myeloma
HIV
Antibiotics
Anticonvulsants
Excess Vitamin C
Nitric Oxide
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
Alzheimer’s Disease
Increased liver weight
Fat accumulation around heart, liver, peripheral nerves
Symptoms/Effects of Vitamin B12
Deficiency
Increase Decrease
Homocysteine Transcobalamin II
MMA Intrinsic factor
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
Treatment
• Supplements
– Oral pills
– Intramuscular
– Intranasal
– Sublingual