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Folic acid (B9)
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
2.
3.
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
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)
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
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
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
31.
32.
33.
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
35.
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
39.
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