vitamin b 12 julie roche 12/7/04. vitamin b 12 cobalamin porphyrin ring cobalt nucleotide net...
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Vitamin B12
CobalaminPorphyrin ringCobaltNucleotideNet charge = +1
Vitamin B12 Derivatives
Cyanocobalamin (digested form)HydroxycobalaminChlorocobalaminMethylcobalaminAdenosylcobalamin
(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)• NMR spectroscopy
• Enzymology• 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
• Methionine
• Methylmalonyl CoA
• Succinyl CoA
The effects of Vitamin B12
on the conversion of homocysteine to methionine
Homocysteine
Methionine
Methylcobalamin
Methionine Synthase
5-methyltetrahydrofolate tetrahydrofolateTetrahydrofolate methyltransferase
The effects of Vitamin B12
on the conversion of Methylmalonyl CoA to Succinyl CoA
Methylmalonyl Co A
Succinyl CoA
Adenosylcobalamin
Methylmalonyl CoA mutase
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
Transcobalamin IR-type binding protein33% is carbohydrateMolecular weight = 125,000-150,000Beta globulinContains more sialic acid than
transcobalamin IIICarries ~80% of Vitamin B12 in blood
Vitamin B12 has half-life of 10-12 days when bound to it
Transcobalamin IIMolecular weight = 38,000Alpha globulinNOT a glycoprotein Carries less than 25% of Vitamin B12 in blood Vitamin B12 has half-life of under 1 ½ hours
when bound to itEncourages absorption in a number of tissuesDegenerates once B12 is released
B12 then recirculatesTranscobalamin II deficiency results in
pernicious anemia
Transcobalamin IIIR-type binding protein33% is carbohydrateMolecular weight = 125,000-150,000Alpha globulinReleased from granulocytesContains more fucose than
transcobalamin I
Antibacterial Roles of Transcobalamin I & III
Binds to large amounts of vitamin B12
and carries it to liverExcreted in bile
Prevents bacteria from using the vitamin for growth
Vitamin B12 separated from Foods in stomach
Binds to Transcobalamin Iand III
Binds to receptors on Liver cells
20% excreted in bile
80% binds to BP & reenters bloodCobalamin
Binding Proteins DegradedWithin 1 ½ hrs
Pinocytosis
Returns to liver or Carried to other tissues
Released and bound to Transcobalamin II
Carried to Ileum and absorbedin by endocytosis
BP degenerates, IF binds to cobalamin
Sources of Vitamin B12
• Fish• Eggs• Meat • Dairy Products
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
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 Kreb’s cycle
Decrease Transcobalamin II Intrinsic factor