2. SOURCES OF FOLIC ACID
Rich sources of folate are yeast,
green leafy vegetables.
Moderate sources are
cereals,pulses,oil seeds and egg.
Milk is a poor source
3. Folate Deficiency
• A serum folate of 3 μg/L or lower indicates deficiency
Folate deficiency may lead to glossitis, diarrhea,
depression, confusion, anemia, and fetal neural tube
defects and brain defects (during pregnancy). Folate
deficiency is accelerated by alcohol consumption. Folate
deficiency is diagnosed by analyzing CBC and plasma
vitamin B12 and folate levels. CBC may indicate
megaloblastic anemia but this could also be a sign of
vitamin B12 deficiency.. Serum folate level reflects folate
status but erythrocyte folate level better reflects tissue
stores after intake. An erythrocyte folate level of 140
μg/L or lower indicates inadequate folate
status. Increased homocysteine level suggests tissue
folate deficiency but homocysteine is also affected by
vitamin B12 and vitamin B6, renal function, and genetics.
4. CAUSES
A deficiency of folate can occur when the body's
need for folate is increased, when dietary intake of
folate is inadequate, or when the body excretes (or
loses) more folate than usual. Medications that
interfere with the body's ability to use folate may
also increase the need for this vitamin
5. Major causes of folic acid deficiency
are as follows:
• 1)PREGNANCY
• 2)DEFECTIVE ABSORBTION:in sprue,celiac diseases,gluten induced
enteropathy ,resection of jejunum and short circuiting of jejunum in
gastroileostomy ,absorption is defective.
• 3)DRUGS:in the diet,folacins are mainly in the polyglutamate
form.GIT enzymes in the gut remove the glutamate residues and
only the monoglutamate form of folic acid is
absorbed.Anticonvulsant drugs (hydantoin,dilantin,phenytoin)will
inhibit the intestinal enzyme,so that folic acid absorption is reduced
• 4)HEMOLYTIC ANEMIAS
• 5)DIETARY DEFICIENCY:absence of vegetables in food for prolonged
periods may lead to defeciency.
• 6)FOLATE TRAP: when vit B12 is deficient ,free THFA is not
generated ,leading to folic acid deficincy.
6. Signs and symptoms
loss of appetite and weight loss can occur. Additional
signs are weakness, sore tongue, headaches,
heart palpitations, irritability, and behavioral
disorders.[2] In adults, anemia (macrocytic, megaloblastic
anemia) can be a sign of advanced folate deficiency.
In infants and children, folate deficiency can slow growth
rate. Women with folate deficiency who
become pregnant are more likely to give birth to low
birth weightpremature infants, and infants with neural
tube defects.
7. Deficiency manifestations
• 1)Reduced DNA synthesis:very rapidly dividing cells in bone marrow
and inestinal mucosa are most seriously effected.
• 2)Macrocytic anemia:It is the most characteristic feature of folic
acid deficiency .During RBC generation.DNA synthesis is delayed
,but protein synthesis is continued .Thus hemoglobin accumulates in
RBC precursors.This asynchrony between the maturity of nucleus
and cytoplasm is manifested as immature looking nucleus and
mature eosinophilic cytoplasm in the bone marrow
cells.Reticulocytes are often seen.Leukopenia and thrombocytopenia
are also manifested.
• 3) Hyperhomocysteinemia:folic acid deficiency may cause increased
homocysteine levels in blood since remethylation of homocysteine in
affected.High plasma homocysteine levels are known to incrase the
risk of coronory aretry diseases.
• 4)Birth defects:folic acid deficiency during pregnancy may lead to
neural tube defects like spina bifida in the foetus.
8.
9.
10.
11.
12. Assessment of folate deficiency
• 1)Blood levels
• 2)Histidine load test or FIGLU excretion test
• 3)AICAR excretion:amino imidazole
carboxamine ribonucleotide accumulates and
is excreted in urine during folic acid deficiency.
13. The role of histidine in the anemia
of folate deficiency
The amino acid histidine is metabolized to glutamic
acid in mammalian tissue. Formiminoglutamic acid
(FIGLU) is an intermediary in this reaction, and
tetrahydrofolic acid is the coenzyme that converts it to
glutamic acid. A test for folate deficiency concerns the
measurement of urinary FIGLU excretion after a
histidine load. FIGLU formed in histidine metabolism
transfers the one carbon fragment,formanino group to
tetrahydrofolate to produce N5-formamino THF
14. Folic acid therapy
• Therapeutic dose is 1mg of folic acid per day
orally.
• Folic acid alone should not be given in macrocytic
anemia,because it may aggrevate the
neurological manifestation of B12 deficiency .
• So,folic acid and vit B12 are given in combination
to patients.
• Regular supplementation of folic acid may reduce
the incedence of birth defects,cardiovascular
diseases and cancers.
15. Folic acid toxicity
• Doses over 1mg may cause aggrevation of
vitamin B12 deficiency and may precipitate
nerve damage
• Since solubility of folic acid is low,large doses
should not be given,as there is danger of
crystallisation in the kidney tubules leading to
renal damage
16. Folate and one-carbon
metabolism
Tetrahydrofolate (THF) polyglutamates are a family of cofactors that carry
and chemically activate one-carbon units for biosynthesis. THF-mediated
one-carbon metabolism is a metabolic network of interdependent
biosynthetic pathways that is compartmentalized in the cytoplasm,
mitochondria, and nucleus. One-carbon metabolism in the cytoplasm is
required for the remethylation of homocysteine to methionine. One-carbon
metabolism in the mitochondria is required for the synthesis of formylated
methionyl-tRNA; the catabolism of choline, purines, and histidine; and the
interconversion of serine and glycine. Mitochondria are also the primary
source of one-carbon units for cytoplasmic metabolism. Disruption of folate-
mediated one-carbon metabolism is associated with many pathologies and
developmental anomalies.
18. Folate Trap
• The conversion of 5,10-methylen-THF into 5-methyl-THF,
which is catalysed by MTHFR, is irreversible. The only way
to make further use of 5-methyl-THF and to maintain the
folate cycle is vitamin-B12-dependent remethylation of
homocysteine to methionine (regenerating THF). The
methyl group transfer is therefore greatly dependent on 5-
methyl-THF and the availability of vitamin-B12. In humans,
this is the only known direct link of the metabolism of two
vitamins; folic acid and vitamin-B12 both need each other.
• In cases of vitamin-B12 deficiency, it is possible that, in spite
of sufficient availability of folates (and 5-methyl-THF), an
intracellular deficiency of biologically active THF arises. This
situation is called a ‘folate trap’
21. Chemistry of Folic acid
• Composed of three constituents- Pteridine group
linked with para amino benzoic acid (PABA) is
called pteroic acid .It is then attached to glutamic
acid to form pteroyl glutamic acid or folic acid .
• In nature,polyglutamates are seen where up to
seven glutamate residues are linked to pteroyl
group.
• Folic acid is soluble in water .
• When exposed to light, it is rapidly destroyed.
22. Absorption
• In the diet, folates exist as polyglutamates and
need to be enzymatically converted into folate
monoglutamates by folate reductase in the
jejunal mucosa in order to be absorbed. In
contrast, folic acid is absorbed two-fold better
than folates. Natural food folates are quite
unstable compounds, so that losses in vitamin
activity can be expected during food processing.
In vegetables, up to 40 per cent of folates can be
destroyed by cooking and in grains/cereals, up to
70 per cent of folates can be destroyed by milling
and baking2,4.
23. • Folate/folic acid is not per se biologically
active, but is converted into dihydrofolate (by
the enzyme dihydrofolate synthetase) in the
liver and into tetrahydrofolate by
dihydrofolate reductase; this reaction is
inhibited by the anti-metabolite methotrexate.
Tetrahydrofolate is converted into 5,10-
methylenetetrahydrofolate by serine
hydroxymethyltransferase5. Tetrahydrofolate
as well as its methylated forms play a crucial
role as methyl(ene) donors.
•
24. FUNCTIONS
• Tetrahydrofolate (THF or FH4) the coenzyme of
folic acid , is actively involved in one carbon
mtabolism.THF serves as an acceptor or donor
unit( formyl , methyl etc.) in a variety if reactions
involving amino acids and nucleotide metabolism.
• The one carbon unit binds with THF at position N5
or N10 of pteroyl structure.The attachment of
formyl at position 5 of THF gives N5-formyl
tetrahydrofolate which is commonly known as
Folinic Acid or Citrovorum Factor.
25. • THF-1carbon derivative R group
• N5 formyl THF -CHO
• N10 formyl THF -CHO
• N5 formimino THF -CH=NH
• N5,N10 methenyl THF =CH2
• N5 methyl THF -CH3
The other commonly found one carbon moities
and there binding with THF are given below :
26. • Many important compounds are synthesised in
one carbon metabolism.
1. Purines which are incorporated into DNA and
RNA.
2. Pyrimidine nucleotide-deoxythymidylic acid (d
TMP), involved in the synthesis of DNA.
3. Glycine, serine, ethanolamine and choline are
produced.
4. N-formyl methionine, the initiator of protien
biosynthesis is formed.
27. • Tetrahydrofolate is mostly trapped asN5-
methyl THF in which form it is present in the
circulation. Vitamin B12 is needed for the
conversion of N5-methyle THF to THF, in a
reaction wherein homocysteine is converted to
methionine. This step is essential for the
liberation of free THF and for its repeated use
in one carbon metabolism. In B12 deficiency,
conversion of N5-methyl THF is blocked.
