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Vitamin B 12. Julie Roche 12/7/04. Vitamin B 12. Cobalamin Porphyrin ring Cobalt Nucleotide Net charge = +1. Vitamin B 12 Derivatives. Cyanocobalamin (digested form) Hydroxycobalamin Chlorocobalamin Methylcobalamin Adenosylcobalamin (5’-deoxyadenosylcobalamin).

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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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13C labeling (1990)

NMR spectroscopy

Enzymology

Molecular genetics

Developments Leading to the Discovery of the Biosynthetic Pathway of Vitamin B12


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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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Homocysteine

Methionine

Methylmalonyl CoA

Succinyl CoA

Vitamin B12 affects two Major Pathways


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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

Cobalamin

20% excreted in bile

80% binds to BP & reenters blood

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

  • Fish

  • Eggs

  • Meat

  • Dairy Products

2.4


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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


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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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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

Symptoms/Effects of Vitamin B12 Deficiency


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Treatment

  • Supplements

    • Oral pills

    • Intramuscular

    • Intranasal

    • Sublingual

1%

500-2000

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