FOLIC ACID
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Q1) What are other names of folic acid? |
A1-
Folic
acid is known as Vitamin B9, folacin, ptero-glutamic
acid, anti anemia factor, L-casei factor etc.
|
Q2) How folic acid was discovered? |
A2-
The discovery of folic acid group of vitamins is the result of many
different investigations. The research proceeded along two chief lines.
1. Certain
substances were found to be essential for the growth of microorganisms,
particularly L casei and streptococcus lactis.
2. Other
investigations dealt with factors found to be necessary in the nutrition of
chicks, guinea pigs, and monkeys. Since these substances were not the same as
the known vitamins. They were given new names as their functions became
apparent.
1931
Wills demonstrated factor form yeast active in treating anemia.
1938 Day et al found yeast or
liver extracts active in treating anemia in monkeys.
1938 Snell and Peterson isolated
L. casei growth factor from liver and yeast.
1938 Snell, Williams, et al
isolated bacterial growth factor similar to L.casei
factor from yeast and name it -folic acid.
Not
until later was it evident that the factor required for chick growth and
bacterial growth factor were probably a single substance.
In
other words, liver factor, fermentation L-casei
factor, vitamin M, factor R, S, U, yeast factor, all are vitamins of the same
group related to folic acid. The generic name preferred to be folacin.
1946
Angier et al isolated petro-monoglutamic acid, proved
structure and synthesized it.
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Q3) What is
the structure of folic acid? |
A3-
·
Folic acid is a
conjugated molecule consisting of a pteridine ring (bicyclic nitrogenous compound) structure linked to para-aminobenzoic acid (PABA) that forms pteroic acid.
·
This pteroic
acid is further conjugated with glutamic acid to form ptero-glutamate
Q4) What are
physical properties of folic acid?
|
A4-
·
It is Yellow crystalline substance,
slightly soluble in water but it’s sodium salt is more
soluble in water.
·
It is inactivated by light.
·
Storing at room temperature a considerable
loss occurs.
·
It is stable in neutral and alkaline
medium.
Q5) What are dietary
sources of folic acid?
|
A5-
Folic acid widely occurs in nature
primarily in leafy (foliage) vegetables, yeast and liver.
High dietary source- (90—300) micro grams/100
gm.
Liver (pork,
lamb, chicken, Beef)
Spinach,
asparagus, yeast
Medium dietary source, 30---90
micro gram/100gm.
Wheat,
lentils, beans, Lima beans, barely, oat etc.
Cauliflower, broccoli, beet, greens
Nuts—peanuts, almonds, walnuts,
Low dietary source- up to 30 micro gram/100 gm
Cheese,
milk, meat
Cabbage, carrots
Q6) what are recommended daily
allowances of folic acid?
|
A6-
Children and adults---require 400 micro gram /day
Pregnancy-------800
microgram/day
Lactation -------500 micro gram/day
Intestinal bacteria synthesize
folic acid.
Q7) How folic acid is absorbed and
transported?
|
A7-
·
Folic acid usually occurs as polyglutamate derivatives with two to seven glutamic acid
residues.
§
These polygutamate
are not absorbable. These compounds are taken up by intestinal mucosal cell and
extra glutamate residues are removed by a enzyme conjugase, a lysosomal enzyme.
§
The removal of glutamate residues makes
folate less negatively charged and therefore readily absorbable.
§
Only 20 to 50 % dietary folacin is
absorbed and is nutritionally available.
§
The free folic acid then reduced to
tetrahydrofolate by the enzyme dihydrofolate reductase and converted to N5-methyl
derivative of tetra hydro folate in intestine and circulated in the plasma.
§
In plasma, about 2/3 of the folate is
protein bound which is taken up by tissues upon requirement.
§
Inside the cells, tetra hydro folate is
found primarily as polyglutamate derivative and it appears to be the
biologically most potent forms.
§
Folic acid is also stored to some extent
as a polyglutamate (pentaglutamate) derivative of TH4 in the liver.
Q8) What is role
of folic acid and one carbon pool?
|
A 8-
The one carbon pool refers to single
carbon units attached to folic acid coenzyme carriers.
·
Single carbon atom can exist in a variety
of oxidation states. These include methane, methanol, formaldehyde, formic acid
and carbonic acid.
[Carbonic acid, the hydrated
form of CO2, is carried by the vitamin biotin, which participates
in carboxylation
reactions but is not considered a member of one carbon pool].
·
It is possible to incorporate carbon units
at each of these oxidation states, except methane (CH4) into other
organic compounds.
·
These single carbon units can be
transferred from carrier compounds such as tetrahydrofolate and S-adenosyl methionine to specific structures that are being
synthesized or modified.
·
There are several active species of the
folic acid group. Different species function as one-carbon carriers in
different metabolic processes.
·
The carbon is carried in a covalent
linkage to one or both of the nitrogen atoms at N5 and N10
positions of the pteroic acid.
Q 9) What are
the different forms of co-enzymes of folic acid?
|
A 9-
Known forms of co-enzymes of folic acid are given as below--
1) 5-
methyl FH4
2) 5-OH
methyl FH4
3) 5,10
methylene FH4
4) 5-10
methynyl FH4
5) 5
formyl FH4
6) 10
–formyl FH4
7) -formimino FH4
Q 10) How different
forms of co-enzymes of folic acid are formed?
|
A 10-
1) Serine is the principal
source of one carbon unit.
Glycine
Serine --------+ TH4
--------------àN5 N10 methylene TH4 (-CH2 group) for purine
synthesis
2) N5 N10
methylene TH4 is an important coenzyme because it can be oxidized to
form N5 N10methenyl FH4 or reduction will
convert it to N5 methyl TH4.
3) N5 N10
methylene TH4 can be oxidize as follows
N5 N10
methylene TH4 + NADP+<=è
N5 N10methenyl FH4 +NADPH+ H+
4) Reduction reaction of N5
methenyl TH4 coenzyme
N5 N10
methylene TH4 + NADPH + H+--------à
N5 methyl TH4 +NAD+ (CH3 group)
5) Hydrolysis of N5
N10methenyl FH4
by a cyclohydrolase yields N5 Formyl FH4 (folanic
acid) and N10 formyl FH4
N5 N10methenyl
FH4 +H2O==== N10 formyl
FH4
6) N10 formyl
TH4 can be formed directly from formate.
Formate + TH4------àN10
formyl TH4 (-CHO group)
7) FH4+ HCOO-+
ATP------àN5 formyl
FH4 + ADP + Pi
Formaldehyde is toxic compound,
which reacts spontaneously with amino groups of proteins and nucleic acids
hydroxymethylating them, and forming
The fundamental biochemical
importance of TH4 is to maintain formaldehyde and format in chemically
poised fates, not so reactive as to have toxic effects on cell but available
for essential processes by specific enzyme action.
8) N5
formimino FH4 -------HC=NH (at N5)
catabolite of histidine forms
formimino FH4
N5
formimino glutamate undergoes deamination to N5
N10methenyl FH4.
In
folic acid deficiency if a loading dose of histidine is given to a patient
urinary excretion of figlu (formimino glutamate) is increased. This figlu
excretion test is useful in the diagnosis of folate deficiency, which
clinically is manifested as a megaloblastic anemia.
Conversion
of coenzymes reaction chart
Q 11) What is metabolic role of folic acid?
|
A 11-
1) Various one-carbon
tetrahydrofolate derivatives are required in biosynthetic reactions. They are required for synthesis of choline,
serine, glycine, purines and dTMP.
2)
Formation of thymidine from uridine
Metylation of deoxy uridine to
thymidine require N5 –N10methylene TH4
3) Synthesis of
formyl-methoinine t RNA for initiation of protein synthesis (N10 Formyl FH4)
it is required for the synthesis of purine nucleotides (N10-formyl
FH4)
4) Conversion of
homocysteine to methionine N5 methyl TH4.
Q 12) What
deficiency manifestation of folic acid are observed?
|
A 12-
Deficiency symptoms are…
1) Glossitis
2) Intestinal
disturbances syndrome characterized by a sore mouth and gastro intestinal
disturbances including periodic diarrhea and steatorrhea
is associated with folate deficiency
3) Leucopenia,
thrombocytopenia
4) Macrocytic
anemia
5) Hydrocephalus
6) Endocrine
disturbances
7) Impairment
of antibody formation
8) Cell
division from metaphase----anaphase is blocked
Q13) Why deficiency of folic acid results in megaloblastic
anemia?
|
A13-
·
The most pronounced effect of folate
deficiency is inhibition of DNA synthesis due to decrease availability of
purines and dTMP.
·
This leads to characteristic megaloblastic
change in size and shape of nuclei of rapidly dividing cells.
·
The block in DNA synthesis slows down
maturation of red blood cells, resulting in production of abnormally large
‘macrocytic’ red blood cells with fragile membranes.
·
Thus macrocytic anemia associated with
megaloblastic changes in the bone marrow is characteristic of folate
deficiency.
Q14) What is role
of folic acid in homocysteinemia?
|
A14-
·
Hyper homocysteinemia
is fairly common in elderly population and appears to be due to inadequate
intake and /or decreased utilization of folate, vitamin B6 and
vitamin B12.
·
Folic acid might prevent heart disease in
adults by lowering levels of an artery damaging substance called homocysteine.
·
Elevated homocysteine levels usually
respond to supplementation with these vitamins.
Q 15) Which
factors are responsible for folic acid deficiency?
|
A 15-
§
Folate deficiency is common in alcoholics,
in malabsorption diseases, due to a combination of poor dietary habits and poor
absorption.
§
Number of drugs that interfere folate
metabolism e.g. anticonvulsants and oral contraceptives. They may interfere
with folate absorption and anticonvulsant appears to increase catabolism of
folate.
§
In disorder of hereditary folate
malabsorption, which may be associated (with a defective carrier), failure of
growth, megaloblastic anemia and severe mental retardation may result.
|
Q 16) For treating
megaloblastic anemia why vitamin B12 should be included with folic
acid |
A 16-
A close relationship exists between
metabolism of the folate and of vitamin B12.
§
Deficiency of either produces
megaloblastic anemia and symptoms of vitamin. B12 deficiency.
§
Anemia is reversed by large doses of
folate; however folate does not reverse the neurological abnormalities, which
are associated with vitamin B12 deficiency hence?????
Q 17) what is
folate trap hypothesis?
|
A17-
The common point in metabolism of folate and vitamin B12 is
methylation of homocysteine to methionine.
§
In human and some other species, this is
the only route for conversion of N5 methyl FH4, to other
folate derivatives.
§
According to methyl folate trap hypothesis,
inhibition of this reaction by cobalamin deficiency leads to accumulation of
folate as N5 methyl FH4, deprives the cell of other
folate cofactors and leads to blockage of several enzymatic reactions. The role
of vitamin B12 and N5-methyl-THF in the conversion of
homocysteine to methionine also can have a significant impact on the ability of
cells to regenerate needed THF.
§
Inherited disorders of folate transport
and metabolism may be due to:
-
Defects in folate carrier (hereditary
folate malabsorption),
-
Deficiency of N5 N10methyleneFH4
reductase
-
Functional deficiency of N5
–methyl FH4 methyl transferase
-
Formimino transferase
-
Or due defects of vitamin B12
metabolism
Q 18) Which analogues compounds of folic
acid are used for therapeutic purposes?
|
A 18-
·
Methothrexate,
a structural analogue of FH2, is a potent inhibitor of di hydro
folate reductase and is used in chemotherapy for neoplastic
disease.
·
Methothrexate
is not effective against bacteria and protozoa infections since these organisms
are impermeable to folate and its analogue.
·
Pyrimethamine
is very effective against protozoan (e.g. malarial parasite) but ineffective
against bacteriaaal infection.it
is mild inhibitor of mammalian enzyme.
·
Trimethoprim-
effective inhibitor for bacteria and protozoal
enzymes but has minimal inhibition against the mammalian enzymes.
These
selective enzyme inhibitors have been used in the treatment of bacterial and
malarial infections.