Topic 5

Vitamin B12
 Vitamins

Definition - Organic compound required in small amounts.

WHY IT'S SPECIAL

IN BIOINORG.
CHEM. ??
Vitamin A

Vitamin B1, B2, B3, B5, B6, B7, B9, B12

Vitamin C

Vitamin D

Vitamin E

Vitamin K
Retinol (vitamin A)

Vitamin B1 - Thiamine

Vitamin B2 - Riboflavin
Vitamin B3 - nicotinic acid

Vitamin B5 - pantothenic acid

Vitamin B6 - pyridoxine

Vitamin B7 - Biotin.
Vitamin B9 - folic acid

Vitamin C - asorbic acid

Vitamin D3 (cholecalciferol) Vitamin D2 (ergocalciferol)
 Vitamin E -

Vitamin K - phylloquinone

ALL VITAMINS CONTAIN NO METALS, EXCEPT VITAMIN B12

 Vitamin B12
Cobalamin
Porphyrin ring
Cobalt
Nucleotide
Net charge = +1
Important in:

– proper nerve function

– production of red blood cells (prevention of anemia)

– metabolizing fats and proteins

–– DNA reproduction
 Vitamin B12 Derivatives
Cyanocobalamin (digested form)
Hydroxycobalamin
Chlorocobalamin
Methylcobalamin
Adenosylcobalamin
 (5’-deoxyadenosylcobalamin)
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Adenosylcobalamin
 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

Vitamin B12
• Produced on an industrial level
• Fermentation
– Methanosarcina
– Butribacterium
– Acetobacterium
– Propionibacterium
• Produces largest amount 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
(enzyme)
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

(enzyme)
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 & Methylmalonic acid
(MMA) excreted in urine
– Diagnosis for cobalamin deficiency
• Methylmalonyl CoA mutase & Methionine
synthase affect amino acid metabolism
– Amino acid metabolism is 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 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 Pinocytosis

Liver cells (small particles suspended in extracellular
fluid are brought into the cell through an
invagination of the cell membrane, resulting
in a suspension of the particles within a
small vesicle inside the cell).

Binding Proteins Degraded

Within 1 ½ hrs
20% excreted in bile
Cobalamin 80% binds to BP & reenters blood

BP=Binding Proteins

BP degenerates, IF binds to Carried to Ileum and absorbed

cobalamin in by endocytosis (the process of actively
transporting molecules
IF=Intrinsic Factor into the cell)

Released and bound to Returns to liver or

Transcobalamin II Carried to other tissues
 Cbl =Cobalamin
TC =Trans Cobalamin
R = Receptor

IF =Intrinsic Factor
HC =Hydro Carbon
ASGP= Asialoglycoprotein

(cell of the main parenchymal

tissue of the liver)
 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
 Causes rise in Kreb’s cycle