Folic acid is a water-soluble B vitamin that acts as a coenzyme in single-carbon transfers in amino acid and nucleotide metabolism. It is required for DNA synthesis and cell division. A deficiency can lead to megaloblastic anemia due to impaired DNA synthesis. Rich dietary sources include green leafy vegetables. Folic acid supplementation is important during pregnancy to prevent neural tube defects in newborns.

1. FOLIC ACID (B9]
Gandham. Rajeev
Department of Biochemistry,
Akash Institute of Medical Sciences &
Research Centre,
Devanahalli, Bangalore,
Karnataka, India.
E-Mail: gandhamrajeev33@gmail.com

4.  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

5.  Tetrahydrofolate (THF or FH4) is the active
form of folic acid
5
10

7. N
H
H
HN
I
H
H2N
N
N
H
I
N
- CH2 – NH-
O
II
- C
H
I
- N - CH –COO-
I
CH2
I
CH2
I
COO-
8
7
6
5
Folic Acid
Dihydrofolate
reductase
2NADPH + 2H+
2NADP
5,6,7,8 – Tetrahydrofolic acid (THF)

8.  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

9.  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)

10.  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)

11.  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)

12.  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

13.  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

14.  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)

15.  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

16.  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

17.  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

18.  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

19.  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

20. Glycine
Tryptophan
Formate N10-Formyl THF
Purine (C2)
Histidine
FIGLU N5-FormiminoTHF N5,N10-Methenyl THF
Serine N5,N10-Methylene THF
Choline
Betaine
N5 Methyl THF
B12
Methionine
S-Adenosyl Methionine
Homocysteine
CH3-
Transmethylation
Formylmethionine
Purines (C8)
Serine
Thymidylate
Major sources
Major Products
THF
THF
THF
THF
One Carbon Metabolism

21.  Rich sources are green leafy vegetables such
as spinach, cauliflower
 Poor sources are liver, kidney, milk, fruits

22. Men -100 µg/day
Women -100 µg/day
Pregnancy -400 µg/day
Lactation -150 µg/day

23.  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

24.  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

25.  Megaloblastic anemia characterized by
hyperchromic macrocytic anemia (due to
maturation bloked)
 Magaloblastic changes are seen in bone
marrow & mucosa
 Patients look pale
 Glossitis

26.  Peripheral smear shows macrocytic
hyperchromic anemia
 Hypersegmentation of neutrophils is common

27.  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

28.  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

29.  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

30.  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

34.  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

36.  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

37.  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

38.  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

40.  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