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Vitamin B12 and Folic Acid
Objectives
1.
2.
3.
4.
5.
Chemistry of vitamin B12
Metabolism of Vit. B12
Functions
Sources and daily requirement
Deficiency
VITAMIN B 12
SYNONYMS:
• Anti – pernicious anemia factor
• Extrinsic factor of Castle
• Animal protein factor
CHEMISTRY
• Vitamin B12 is water soluble, heat stable
and red in color.
• It contains 4.35 % cobalt by weight.
• It contains 63 carbon, 14 nitrogen and
one cobalt atoms.
• Four pyrrole rings co-ordinated with
cobalt atom is called a corrin ring.
CHEMISTRY
• The 5th valency of the cobalt is
covalently linked to a substituted
benzamidazole ring.
• This is then called cobalamin.
• The sixth valency of the cobalt is
satisfied by any of the following
groups: cyanide, hydroxyl, adenosyl or
methyl.
CYNO COBLAMIN
• When cyanide is added at the R
position,
the
cynocobalamine
molecule
is
called
HYDROXY COBLAMIN
• When hydroxyl group is attached at the
R position, it is called hydroxy
coblamin.
• When taken up by the cells, these
groups
are
removed
and
deoxyadenosyl coblamin is formed.
METHYL COBLAMIN
• When the methyl group replaces
adenosyl group, it is known as methyl
coblamin.
• This is the major form seen in blood
circulation as well as cytoplasm.
RDA
• Normal daily requirement is 1 – 2 μg /
day.
• During pregnancy and lactation, this is
increased to 2 μg / day.
DIETARY SOURCES
• Vitamin
B12
is
not
present
in
vegetables.
• Liver is the richest source.
• Meat, fish and egg are good sources.
• Curd is also good source, because
lactobacillus can synthesize B12.
ABSORPTION OF VITAMIN B12
• Vitamin B12 combines with the intrinsic
factor (IF) of castle.
• Hence the B12 is otherwise is known as
extrinsic factor (EF), that is the factor
derived from external sources.
• Intrinsic factor is secreted by the
gastric parietal cells.
• It is a glycoprotein with a molecular
weight of 50,000.
• One molecule of IF can combine with
two molecule of vitamin B12.
• This IF-B12 complex is attached with
specific receptor on mucosal cells.
• The IF-B12 complex is internalized.
• It may be noted that, vitamin B12 is
absorbed from ileum, while folic acid is
from jejunum.
TRANSPORT & STORAGE
• The IF is digested inside the mucosal
and B12 is transported to the
circulation.
• In the blood methyl B12 form is
predominant.
• Transcobalamin II, a glycoprotein, is
the specific carrier.
• It is stored in the liver cells, as ado-B12
form,
in
combination
with
Transcobalamin I.
• Generally, B complex vitamins are not
stored in the body, B12 is an exception.
• Whole liver contain about 2 mg of B12
• Which
is
the
sufficient
for
the
requirement for 2 – 3 years.
• So, B12 deficiency is seen only years
after gastrectomy.
BIOCHEMICAL FUNCTIONS
• Synthesis of Methionine from homocystine:
THF
N5 METHYL THF
Homocysteine
METHIONINE
Methyl Coblamin
B12
FOLATE TRAP
BIOCHEMICAL FUNCTIONS
• Vitamin
B12
deficiency
leads
to
impairment of Methionine synthase,
resulting
in
accumulation
of
Homocysteine and trapping folate as
methyl tetra hydrofolate.
• This known as folate trap.
BIOCHEMICAL FUNCTIONS
• ISOMERISATION
OF
METHYL
MALONYL COA TO SUCCINYL COA
DEFICIENCY
MANIFESTATIONS
•
•
•
•
•
•
•
Adult pernicious anemia
Mucosal atrophy of stomach
Glossitis, hypersegmented neutrophils
Stomatitis
Pharyngitis
Achlorhydria
Folate Trap
DEFICIENCY
MANIFESTATIONS
• Damage to nervous system, the sub
acute combined degeneration.
• Demyelination and neural death.
• Mild deficiency may cause depression,
confusion and less alertness.
Peripheral
blood
smear
showing
hypersegmented neutrophils, characteristic
of megaloblastic anemia.
Megaloblastic anemia
CAUSES OF B12 DEFICIENCY
NUTRITIONAL:
• Vitamin B12 deficiency is very common
in India, especially among vegetarians
of low socioeconomic group.
• The only source for B12 in vegetarian
diet is curd/ milk and lower income
group may not able to afford it.
CAUSES OF B12 DEFICIENCY
•
•
•
•
•
•
•
Decrease in absorption
Elderly people
Addisonian pernecious anemia
Gastric atrophy
Fish tapeworm
Pregnancy
Inherited defects
FISH TAPEWORM
FISH TAPEWORM
FISH TAPEWORM
TREATMENT
• If megaloblastic anemia is treated with
folic acid alone, the anemia may
improve, but associated nervous
lesions are aggravated.
• Hence all macrocytic anemia's are
generally treated with Folate and
vitamin B12.
• Therapeutic dose of B12 is 100 – 1000
microgram by intramuscular injection.
Folic Acid
Objectives
1.
2.
3.
4.
5.
6.
Chemistry
Metabolism
Functions
Sources and daily requirement
Deficiency
Folic acid antagonist
FOLIC ACID
SYNONYMS:
• Liver lactobacillus
• Caseifactor
• Vitamin M
• Streptococcus Lactis R (SLR)
factor
• pteroyl glutamic acid (PGA).
FOLIC ACID CHEMISTRY
The designation folic acid is applied to a
number of compounds which contain
the following group.
• Pteridine nucleus
• Para Amino Benzoic Acid
• Glutamic Acid
RDA
• Adults
: 400 – 500 μg/ day
• Infants
: 50 μg/ day
• Children
: 100 – 300 μg/ day
Requirement increases in pregnancy &
lactation
• Pregnant women : 800 μg/ day
• Lactating women: 600 μg/ day
DIETARY SOURCES
• Folic acid is widely distributed in
nature.
• Rich
sources
are
green
leafy
vegetables, whole grains, cereals, liver,
kidney, yeast and eggs. Milk is rather
poor source of folic acid.
ABSORPTION, TRANSPORT
AND STORAGE
• Most of the dietary folic acid found as
polyglutamate with 3 – 7 glutamate
residues is not absorbed in the
intestine.
• The enzyme folate conjugase present in
duodenum and jejunum split the
glutamate residues.
• Only the monoglutamate of folic acid is
absorbed from the intestine.
BIOCHEMICAL FUNCTIONS
• Tetrahydrofolate, the coenzyme of folic acid is
actively involved in the one carbon
metabolism.
• THF is serves as an acceptor or donor of one
carbon units (formyl, methyl etc.).
COMPOUND SYNTHESIZE IN 1 CARBON METABOLISM:
1. Purines ( carbon 2 & 8), deoxy thymydylic acid.
2. Glycine, serine, ethanolamine and choline.
3. N – formylmethionine.
DEFICIENCY SYMPTOMS
• In folic acid deficiency, decreased
production of purines and dTMP is
observed
which
impairs
DNA
synthesis.
• Due to block in DNA synthesis, the
maturation of erythrocytes is slowed
down leading to macrocytic RBC.
NORMAL RBC SMEAR
MACROCYTIC ANEMIA
SPINA BIFIDA
• Folic
acid
deficiency
during
pregnancy may lead to neural tube
defects in the fetus.
• Folic acid prevents birth defects,
fetal malformations such as spina
bifida.
• So, high doses of folic acid are
recommended in pregnancy.
SPINA BIFIDA
RISK OF EXCESS OF FOLIC
ACID
• Irreversible nerve damage.
• Solubility of folic acid is low, hence
large doses of folic acid if given
parenterally
there
is
risk
of
crystallization in kidney tubules leading
to renal damage.
Folic Acid Deficiency and Homocysteinimia
HOMOCYS.– A RISK FACTOR FOR CHD
Folic Acid antagonist
•Aminopterin and Amethopterin (Methotrexate)
Clinical Use:inhibit DNA synthesis especially in
cancer cell.
•Trimethoprim
Clinical Use: used to treat for bacterial
infections along with sulfomethaxozole
VITAMIN LIKE COMPOUNDS
CHOLINE
• Choline
is
trimethyl
hydroxy
ethanolamine.
• Best and Huntsman (1934) found that,
Choline deficiency in rats produced
fatty liver and established its nutritional
importance.
STRUCTURE OF CHOLINE
CH3
H3C
N+
CH3
CH2
CH2
OH
BIOCHEMICAL FUNCTIONS
• Choline,
as
a
component
of
phospholipids is involved in membrane
structure and lipid transport.
• Due to the presence three methyl
groups, choline is actively involved in
one carbon metabolism.
• Choline is a precursor for the synthesis
of acetylcholine which is required for
transmission of nerve impulse.
INOSITOL
• Inositol is hexahydroxy – cyclohexane.
• It is also known as myo – Inositol or
meso – inositol.
STRUCTURE OF INOSITOL
BIOCHEMICAL FUNCTIONS
• Inositol is required for the synthesis of
phosphatidyl Inositol which is a
constituent of cell membrane.
• It act as a lipotropic factor ( along with
choline) and prevents the accumulation
of fat in liver.
BIOCHEMICAL FUNCTIONS
• For some hormones, inositol act as a
second messenger at the membrane
level for the release of Ca2+ ions.
LIPOIC ACID
• Lipoic acid is a sulphur containing fatty
acids.
• It exists in an oxidized and reduced
form.
• Lipoic acid is fat as well as water
soluble.
STRUCTURE OF LIPOIC ACID
BIOCHEMICAL FUNCTIONS
• Lipoic
acid
is
involved
in
the
decarboxylation reactions along with
other vitamins.
• The conversion of pyruvate to acetyl
CoA and α – ketogluterate to succinyl
CoA require LIPOIC ACID.
PARA AMINO BENZOIC ACID
• Para amino benzoic acid (PABA) is a
structural constituent of folic acid.
• The deficiency of PABA was first found
to
be
associated
with
failure
lactation graying of black hair in rats.
of
PARA AMINO BENZOIC ACID
PARA AMINO BENZOIC ACID
• PABA is synthesized by the bacteria
and is essential for their growth.
• The sulfa drug sulfonilamide is a
structural analogue of PABA.
BIOFLAVONOIDS
• Szent – Gyorgi and his associates
(1936) observed that, flavonoids,
isolated from lemon peel were
responsible for maintenance of normal
capillary permeability.
• The term vitamin P was used to this
group of substance.
• However, they are commonly known as
BIOFLAVONOIDS.
BIOFLAVONOIDS
BIOFLAVONOIDS
BIOCHEMICAL FUNCTIONS
• Bioflavonoids act as antioxidant and
protect
ascorbic
acid
from
being
destroyed.
• It is suggested that, this antioxidant
property
may
be
responsible
for
maintenance of capillary permeability.