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FOLIC ACID (B9]
Gandham. Rajeev
Department of Biochemistry,Akash Institute of Medical Sciences & Research Centre,Devanahalli, Bangalore, Karnataka, India.
E-Mail: [email protected]
Folic acid ( B9 )
Chemistry
The word folic acid is derived from latin
word Folium means leaf & it is also
isolated from the leafy vegetable spinach
Folic acid mainly consists of three
components
Pteridine ring
PABA (p-amino benzoic acid)
Glutamic acid residue (1 to 7 residues)
Hence it is known as Pteroyl-glutamic acid
ACTIVE FORM
Tetrahydrofolate (THF or FH4) is the active
form of folic acid
5
10
NH
H
HNIH
H2N
N
N
HIN
- CH2 – NH-
O II- C
H I - N - CH –COO-
ICH2
ICH2
ICOO-
87
65
Folic Acid
Dihydrofolate reductase
2NADPH + 2H+
2NADP
5,6,7,8 – Tetrahydrofolic acid (THF)
METABOLISM
Absorption:
Formation of monoglutamate form:
Most of the dietary folic acid exists as
polyglutamate with 3-7 glutamate
residues
It is not absorbed in the intestine
The glutamate side chains are cleaved
by the enzyme folate conjugase or
polylpolyglutamate hydrolase
Only monoglutamyl form of folic acid is
absorbed from the intestine
The enzyme folate conjugase is present in
duodenum & jejunum
Mucosal uptake & metabolism in mucosal
cell
Folate monoglutamate is taken up by the
mucosal cell
In the mucosal cell, folate monoglutamate
is reduced to tetrahydrofolate &
methylated to form N5 methyl
tetrahydrofolate (in circulation)
N5 methyl tetrahydrofolate enters the
circulation
Storage:
Inside the cells, tetrahydrofolates are
found as polyglumates (with 5-6 amino
acid residues)
Which are biologically most potent
Polyglutamate is the storage form of folic
acid
It is mainly stored in the liver (10-20 mg)
Biochemical functions
Folic acid is not biologically active
The active coenzyme forms of folic acid
are
Tetrahydrofolic acid (FH4)
N5 methyl tetrahydrofolic acid (N5FH4)
N5,N10 methylene tetrahydrofolic acid
N10 formyl tetrahydrofolate(N10 formyl FH4)
N5 formimino tetrahydrofolate (N5
formimino FH4)
N5 formyl tetrahydrofolate (N5 formyl FH4)
N5,10 methenyl tetrahydrofolate N5,10
methenyl FH4)
N5 formyl THF -CHO
N10 formyl THF -CHO
N5 formimino THF -CH=NH
N5,N10 methenyl THF= CH
N5,N10 methylene THF =CH2
N5 methyl THF - CH3
The coenzymes of folic acid are actively
involved in the one carbon
metabolism
THF acts as an acceptor or donor of one
carbon units (formyl, methyl etc.) in
reactions involving amino acid &
nucleotide metabolism
The one carbon units bind with THF at
position N5 or N10 or on both N5 &N10
of pteroyl structure
ONE CARBON METABOLISM
Amino acid metabolism is important for
transfer or exchange of one carbon units
The following one carbon fragments are
involved in biological reactions
Methyl (-CH3)
Hydroxymethyl (-CH2OH)
Methylene (=CH2)
Methenyl (-CH=)
Formyl (-CH=O)
Formimino (-CH=NH)
THF is a versatile coenzyme actively
participates in one carbon metabolism
Transfer of methyl groups from S-
adenosylmethionine
B12 is also involved
The one carbon units covalently binds
with THF at position N5 or N10 or on
both N5 &N10 of pteroyl structure of
folate
GENERATION OF ONE CARBON UNITS
Many compounds particularly amino acids
act as donors of one carbon units
The formate is released from glycine &
tryptophan metabolism combines with THF
to form N10 – formyl THF
Histidine contributes formimino fragment to
produce N5 – formimino THF
Serine is converted to glycine, N5,N10
methylene THF is formed
This is most common entry of 1C units into
one carbon pool
Choline contributes to the formation of
N5 methyl THF
Different derivatives of THF carrying one
carbon units are interconvertible, & this
is metabolically significant for the
continuity of one carbon pool
Utilization of one carbon units Utilized for synthesis of wide variety of
compounds
These includes
Purines
Formylmithionine tRNA (initiation of
protein synthesis)
Glycine
Pyrimidine nucleotide etc
Role of methionine & vitamin
B12 Methyl group is an important one carbon
unit
Methionine is active donor of methyl
groups in transmethylation reactions
After the release of methyl group,
methionine is converted to
homocysteine
For regeneration of methionine,
homocysteine & N5-methyl THF are
required & this reaction is dependent on
Vitamin B12
The one carbon pool, under the control
of THF, is linked with methionine
metabolism through Vitamin B12
GlycineTryptophan
Formate N10-Formyl THF
Purine (C2)
Histidine
FIGLU N5-FormiminoTHF N5,N10-Methenyl THF
Serine N5,N10-Methylene THF
CholineBetaine
N5 Methyl THF
B12
Methionine
S-Adenosyl Methionine
Homocysteine
CH3-
Transmethylation
Formylmethionine
Purines (C8)
Serine
Thymidylate
Major sourcesMajor Products
THF
THF
THF
THF
One Carbon Metabolism
DIETARY SOURCES
Rich sources are green leafy vegetables
such as spinach, cauliflower
Poor sources are liver, kidney, milk,
fruits
RDA
Men -100 µg/day
Women -100 µg/day
Pregnancy -400 µg/day
Lactation -150 µg/day
DEFICIENCY
Dietary deficiency is the most common
cause of folic acid
Dietary deficiencies are caused by
Inadequate intake seen in alcoholics
Overcooking of food resulting in loss of
folic acid activity
Impaired absorption due to small intestinal
diseases,
Drugs interfere with folic acid absorption-
sulfamethaxazole
Increased demand of folic acid seen in
pregnancy
Hemolytic anemia
Hence folic acid preparations are
prescribed in pregnancy &hemolytic
anemia
Other causes
Loss of folic acid seen in patients
undergoing dialysis
Impaired synthesis of active form seen in
patients receiving folic acid antagonists
such as methotrexate
CLINICAL FEATURES
Megaloblastic anemia characterized by
hyperchromic macrocytic anemia (due
to maturation bloked)
Magaloblastic changes are seen in bone
marrow & mucosa
Patients look pale
Glossitis
LABORATORY FINDINGS
Peripheral smear shows macrocytic
hyperchromic anemia
Hypersegmentation of neutrophils is
common
Bone marrow shows megaloblastic
changes characterized by abnormally
large size of erythroid cells with
cytoplasmic maturation but impaired
nuclear maturation due to defective
DNA synthesis
Defective red cell production
BIOCHEMICAL FINDINGS
Low plasma folic acid levels (<3ng/ml)
Low red cell folic acid levels (<150
ng/ml)
Normal plasma Vitamin B12 levels
Increased plasma LDH levels
FIGLU excretion test:-
Folic acid deficiency is associated with
increased excretion of
formiminoglutamate (FIGLU) in urine
Due to impaired conversion of FIGLU to
glutamate in a reaction requiring FH4
Histidine
FIGLU
Formimino FH4
Histidine
Glutamate
FH4
FIGLU
Formimino FH4
Glutamate
FH4
Urine
Folic acid deficiency
FOLIC ACID DEFICIENCY & NEURAL TUBE DEFECTS
Folic acid supplementation during
pregnancy helps to prevent neural tube
defects
Mainly involved in brain & spinal cord
Science, folic acid involved in nucleic acid
& amino acid metabolism
Deficiency results in impaired & aberrant
neural development
FOLIC ACID DEFICIENCY & HOMOCYSTEINEMIA
Homocysteine is a risk factor for CHD
Folic acid is required for conversion of
homocysteine to methionine
Deficiency is associated with increased
plasma levels of Homocysteine
Folic acid suplementation decreases
plasma homocysteine levels
Homocysteine levels are also increased
in Vitamin B12 & Pyridoxine deficiency
FOLIC ACID ANTAGONISTS
Aminopterin & Amethopterin
(methotrexate)
Aminopterin & Amethopterin
(methotrexate) competitevely inhibit the
enzyme dihydrofolate reductase in
humans
It impaires the formation of active form of
tetrahydrofolate from dihydrofolate
Significance:-
During the conversion of deoxyuridylate
to deoxythymidylate, dihydrofalate is
formed, utilizes N5,10 methylene FH4
Deoxythymidylate is required for DNA
synthesis
Folic acid antagonists will block DNA
synthesis & inhibit cell division
Clinical uses:-
Aminopterin & Amethopterin
(methotrexate) inhibit DNA synthesis in
cancer cells
Used in treatment of cancer
Particularly leukemia & choriocarcinoma
TRIMETHOPRIM
It is a folic acid antagonist & it inhibits
the bacterial dihydrofolate reductase
Thus impairs the deoxythymidylate
synthesis leading to decreased synthesis
of DNA
It is mainly used in bacterial infections
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