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Vitamin B12 T.Y. B.Sc. Rayat Shikshan sanstha’s
S.M. Joshi College, Hadapsar, Pune. Chemistry Department Vitamin B12 T.Y. B.Sc. Dr. Ranjana K. Jadhav Dept. of Chemistry S. M. Joshi College, Hadapsar, Pune.
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Vitamin B12 Cobalamin Porphyrin ring Cobalt Nucleotide Net charge = +1
Cobalamin Porphyrin ring Cobalt Nucleotide Net charge = +1 Also known as cobalamin
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physiological useful forms
Vitamin B12 Derivatives Cyanocobalamin (digested form) Hydroxycobalamin Chlorocobalamin Methylcobalamin Adenosylcobalamin (5’-deoxyadenosylcobalamin) physiological useful forms Derivatives are formed by attaching an atom to the cobalt
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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 Molecular oxygen only needed in aerobic Between intermediates precorrin 3a and precorrin 3b Synthesis is more difficult without oxygen *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 Developments led to discovery of B12 synthesis Carbon 13 labeling…. Once compound was labeled… could follow it through the synthesis using NMR spec
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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 Produced on industrial level to provide supplements for patients with B12 deficiency Bacterial fermentation Bacteria used in the past years Trying to lower propionic acid conc and still make B12
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Vitamin B12 affects two Major Pathways
Homocysteine Methionine Methylmalonyl CoA Succinyl CoA Conversion of
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The effects of Vitamin B12 on the conversion of homocysteine to methionine
Methionine Synthase Methylcobalamin Methionine In conversion of homocysteine to methionine… enzyme is methionine synthase, and cofactor is methylcobalamin (physiological useful form) Once methionine is made it stimulates another pathway from 5-methyltetrahydrofolate to tetrahydrofolate 5-methyltetrahydrofolate tetrahydrofolate Tetrahydrofolate methyltransferase
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The effects of Vitamin B12 on the conversion of Methylmalonyl CoA to Succinyl CoA
Methylmalonyl CoA mutase Adenosylcobalamin Succinyl CoA In the conversion of methylmalonyl coA to succinyl coA… enzyme is methylmalonyl coA mutase and cofactor is adenosylcobalamin (other physiological useful form) Succinyl coA then enters krebs cycle 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 Increase in homocysteine and Methylmalonyl CoA because they are not converted
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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 In case of deficiency, aa metabolism is also inhibited
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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 Beta globulin Contains more sialic acid than transcobalamin III Carries ~80% of Vitamin B12 in blood Vitamin B12 has half-life of days when bound to it Sialic acid – amino carbohydrates
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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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Graph showing relative amts of B12 carried by TC I and TC II
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Transcobalamin III R-type binding protein 33% is carbohydrate
Molecular weight = 125, ,000 Alpha globulin Released from granulocytes Contains more fucose than transcobalamin I Fucose is an aldose with formula of C6 H12 O5
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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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Pinocytosis Cobalamin 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 Cobalamin 20% excreted in bile 80% binds to BP & reenters blood Pathway vitamin b12 follows when it is ingested Other tissues- such as bone marrow (b12 is important for RBC synthesis) BP degenerates, IF binds to cobalamin Carried to Ileum and absorbed in by endocytosis Released and bound to Transcobalamin II Returns to liver or Carried to other tissues
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Sources of Vitamin B12 2.4 Fish Eggs Meat Dairy Products
Fish Eggs Meat Dairy Products 2.4 2.4 micrograms/day
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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 Chron’s disease Pancreatitis Gastric lymphoma Myeloma HIV Antibiotics Anticonvulsants Excess Vitamin C Nitric Oxide Proton pump inhibitors- for GERD (common in elderly) Vit C inactivates B12 Oxidizes B12
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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 Alzheimer’s 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 Kreb’s cycle Decrease Transcobalamin II Intrinsic factor
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Treatment 1% 500-2000 3-7 days... monthly... 4x year Supplements
Oral pills Intramuscular Intranasal Sublingual 1% 3-7 days... monthly... 4x year micrograms/day Large amount is needed cuz only 1% is absorbed
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