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COBALAMINE (B12]
Gandham. Rajeev
Department of Biochemistry,Akash Institute of Medical Sciences & Research Centre,Devanahalli, Bangalore, Karnataka, India.
E-Mail: [email protected]
Vitamin B12
Cobalamin
Extrinsic factor (EF) of castle
Antipernicious anemia factor
Chemistry:
Vitamin B12 is water soluble, heat stable
and red in colour
It contains 4.35% cobalt by weight
Four pyrrole rings co-ordinated with a
cobalt atom is called as a Corrin ring
Synonyms of Vitamin B12
The corrin ring has four pyrrol units, like
porphyrin
Two of the pyrrole units (A&D) are directly
bound to each other where as the other two
(B & C) are held by methene bridges
The groups namely methyl, acetamide and
propionamide are the substituents on the
pyrrole rings
Cobalt present at the centre of the corrin
ring is bonded to the four pyrrole nitrogens
Cobalt also holds dimethyl benzimidazole
(DMB) containing ribose 5-Phosphate and
amino isopropanol
A nitrogen atom dimethyl benzimidazole is
linked to cobalt
The amide group of aminoisopropanol
binds with D ring of corrin
The cobalt atom also possesses a sixth
substituent group located above the plane
of the corrin ring
A
D
B
C
Aminoisopropanol
Methyl, Adenosine, acetamide, propionamide
Aminoisopropanol
dimethyl benzimidazole
D
BA
C
All the forms of vitamin B12 are called
cobalamins because of the presence of
cobalt atom
Different forms of cobalamins include
Cyanocabalamin:- It refers to the isolated
form of vitamin B12 in which cyanide was
added to promote crystallization of
cobalamin during the isolation process
Hydroxycobalamin:- It was usually present in
the tissues and in the naturally occurring
forms of Vitamin B12
Methylcobalamin :- Methyl group replaces
adenosyl group
Adenosyl cobalamin (Ado-B12):-
When taken up by the cells, these groups
are removed and deoxy adenosyl
cobalamin or Ado-B12 is formed
In the food, vitamin B12 is present as a
complex with proteins
The free form of vitamin B12 is released by
cooking, HCL present in gastric juice and
proteolysis by pepsin in the stomach
Mechanism:-
The absorbance of vitamin B12 requires
intrinsic factor
Intrinsic factor is a glycoprotein secreted by
parietal cells of stomach
metabolism
Vitamin B12 combines with intrinsic factor
The vitamin B12 – intrinsic factor complex
reaches the ileum where it is absorbed
In the ileum, the complex attaches to a
specific receptor and is taken up by the
mucosal cell.
In the mucosal cell, vitamin B12 is released
from its complex and reaches the portal
circulation
In the portal blood, it is transported in
combination with transcobalamin II
Vitamin B12 is presented to cells where it is
taken up by the cells through receptor
mediated endocytosis
Storage:
It is mainly stored in liver, leukocytes and
gastric mucosa
It is stored as complex with transcobalamin-
I&II
Transport
ProteinB12
B12
B12
B12
Protein
IF
IF
IF
Mucosal cellB12
Methyl B12B12
B12
TC 1-B12(90%)
TC 1-B12(90%)
TCII -B12(10%)
TCII -B12(10%)
Tissues
B12
TCII
Methyl B12
Deoxyadenosyl
B12(LIVER)
GIT
Plasma Tissues
About 10 enzymes requiring vitamin B12
have been identified
Most of them are found in bacteria ( mutase,
ribonucleotide reductase, etc.)
There are two reactions in mammals that
dependent on vitamin B12
Biochemical functions
Methyl cobalamin is essential for the
conversion of homocysteine to methionine
and formation of FH4 from methyl FH4
The reaction is catalyzed by homocysteine
methyl transferase
Synthesis of Methionine from homosysteine
Homocysteine
Homocysteine methyl transferase
Methionine
methylcobalamin
THFN5 methyl THF
The circulating methyl FH4 is converted to FH4
FH4 is either used for storage as
folylpolyglutamate form or it is utilized for other
reactions such as formation of methylene FH4
Methyl folate trap:-
In B12 deficiency, impaired conversion of methyl
FH4 to FH4 results in accumulation of methyl
FH4 & is called as methyl folate trap
Methyl folate trap results in decreased availability
of FH4 & FH4 derivatives that are
Significance of the reaction
Needed for purine nucleotide & thymidylate
synthesis
Thus vitamin B12 deficiency, results in
secondary folate deficiency
Role of methyl cobalamin & folate trap
Methyl FH4
FH4
N5,10 methylene FH4dUMP
dTMP
DNA
Homocysteine
Methionine
Methylfolate trapMethyl FH4
Homocysteine methyl transferase
FH4
Serine
Glycine
Thymidylate synthase
B12
Isomerization of methyl CoA to succinyl
CoA:-
The degradation of odd chain fatty acids
and some amino acids (valine, leucine etc)
and pyrimidines (thymine & Uracil) produce
propionyl CoA, an imp. Compound
methylmalonyl CoA
The methyl malonyl CoA mutase converts
methyl malonyl CoA to succinyl CoA in the
presence of Vitamin B12,deoxyadenosyl
cobalamin
In B12 deficiency, methyl malonyl CoA
accumulates and is excreted in urine as
methyl malonic acid
This condition is called as methylmalonic
aciduria, occurs in B12 deficiency.
Demyelination :- Myelination of nerves is
impaired in B12 deficiency due to accumulation
of methylmalonyl CoA
Demyelination is due excessive accumulation
of methylmalonyl CoA
Odd chain FA
Propionyl CoA
Amino acids(Val, Ile, Thr,
Met)Thymine,
uracil
Methyl malonyl CoA
Succinyl CoA
Methyl malonyl CoA mutase
Methyl malonic acid
Excreted in urine
5-Deoxyadenosylcabalamin (of B12)
+ Methylmalonic aciduria
Rich sources of vitamin B12 are meats, egg,
milk, sea foods
B12 is synthesized by microorganisms
Vitamin B12 is not present in Plant sources
Dietary sources
Adults -1 µg/day
Pregnancy & lactation -2 µg/day
Causes:
Inadequate intake-seen in pure vegetarians
and rarely in alcoholism
Impaired absorption
This is mainly caused by lack of intrinsic factor
Lack of intrinsic factor is called as pernicious
RDA
Deficiency
anemia & it is caused by destruction of gastric
mucosa
Impaired absorption is also seen in small
intestinal disorders
Impaired storage and transport:
Inadequate utilization of vitamin occurs because
of liver diseases and abnormalities of transport
proteins
Increased requirements are seen in
hyperthyroidism, infancy & thalassemia
Increased excretion occurs in nephrotic syndrome
Vitamin B12 deficiency is characterized by
Megaloblastic anemia:
Feature of megaloblastic anemia include
pallor,fatigue, glossitis ( beefy red tongue) &
slight yellow discoloration of the conjunctiva
due to increased unconjugated bilirubin
Progression of anemia may result in angina
& congestive cardiac failure
Clinical Features
Gastrointestinal dysfunction:
GIT epithelial cells are undergoing rapid
turnover
& dependent on vitamin B12
B12 deficiency results in weight loss &
diarrhea
Demyelination of nervous tissue
Subacute combined degeneration:
Damage to nervous system is seen in B12
deficiency
There is demyelination affecting cerebral
cortex as well as dorsal column & pyramidal
tract
Symmetrical paresthesia of extremities,
alterations of tendon & deep senses &
reflexes, loss of position sense, unsteadiness
in gait, positive Romberg’s sign & positive
Babinski’s sign are seen
Achlorhydria:
Absence of acid in gastric juice is associated
with B12 deficiency
Romberg’s sign & positive Babinski’s sign
Serum B12: It is quantitated by radio-
immunoassay or by ELISA
Methyl melonic acid is excreted in urine
FIGLU excretion test
Peripheral smear: Peripheral blood & bone
marrow morphology shows magaloblastic
anemia
Homocysteinuria: Excretion of
homocysteine in urine
Assessment of B12 deficiency
Schilling test:
Radioactive labelled (Cobalt-60) vitamin B12
1μ g is given orally
In gastric atrophy cases, there is no
absorption, hence the entire radioactivity is
excreted in faeces & radioactivity is not
observed in liver
If the cause is nutritional deficiency, there
will be increased absorption
Then radioactivity is noted in the liver region,
with very little excretion in feces
References
Harper’s Biochemistry 25th Edition.
Fundamentals of Clinical Chemistry by Tietz.
Text Book of Medical Biochemistry-A R Aroor.
Text Book of Biochemistry-DM Vasudevan
Text Book of Biochemistry-MN Chatterjea
Text Book of Biochemistry-Dr.U.Satyanarana