Folate

folic acid

1. FOLIC ACID PRESENTED BY: MEGHNA SINGLA MEHAK KALEKA NAIN AULAKH NEHA NITISH SHARMA (91)

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 μ g/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 B 12  and folate levels. CBC may indicate megaloblastic anemia but this could also be a sign of vitamin B 12  deficiency.. Serum folate level reflects folate status but erythrocyte folate level better reflects tissue stores after intake. An erythrocyte folate level of 140 μ g/L or lower indicates inadequate folate status. Increased homocysteine level suggests tissue folate deficiency but homocysteine is also affected by vitamin B 12  and vitamin B 6 , 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 l oss 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 weight premature  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. 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.

9. 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

10. 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.

11. 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

12. 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 .

13. One carbon metabolism

14. 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’

15. Folate trap

16. Structure of Folic Acid

17. 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.

18. 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 baking 2 , 4 .

19. 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 hydroxymethyltransferase 5 . Tetrahydrofolate as well as its methylated forms play a crucial role as methyl( ene ) donors.

20. 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 .

21. 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 :

22. 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.

23. 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.