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Folic acid

Folic acid. Omar A Obeid NFSC 315. Folic acid. Wills factor (1937): macrocytic anemia in Hind women… respond to Marmite Vitamin M: prevention of anemia in monkeys Vitamin Bc: prevention of anemia in chicks 1943: Purification and crystallization 1946: Synthesis and structure identification.

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Folic acid

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  1. Folic acid Omar A Obeid NFSC 315

  2. Folic acid • Wills factor (1937): macrocytic anemia in Hind women… respond to Marmite • Vitamin M: prevention of anemia in monkeys • Vitamin Bc: prevention of anemia in chicks • 1943: Purification and crystallization • 1946: Synthesis and structure identification

  3. Folic Acid • Synthetic, oxidized form of folate • Pteroylmonoglutamate • Used in supplementation and fortification • Most stable • Composed of three parts • Pteridine ring • p-aminobenzoic acid (PABA) • Glutamic Acid • Must be reduced and glutamated prior to use by body

  4. O OH OH HN O O HN N N N N OH H2N Folic Acid

  5. Folate • Parent Name for all folate co-enzymes • 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) • Principal folates in foods are N5-methyl-THF and N10-formyl-THF • Exist as reduced, polyglutamates

  6. Biosynthesis of folic acid in plants and microorganisms ATP CoASH p- aminobenzoic p- aminobenzoyl p - aminobenzoyl acid AMP AMP CoA glutamic acid Pteroylglutamic acid p- aminobenzoyl glutamic acid

  7. Sources • Folates: variety of foods from plant and animal origin. Exclusively in reduced form as polyglutamyl derivatives of tetra-hyrofolic acid (THF). • Mainly: 5-methyl-THF and 10-formyl-THF • Animal: about 40% methyl derivatives • Plants: both methyl and formyl derivatives • Food Sources • Green, leafy vegetables • Orange Juice • Legumes • Fortified breads and cereals in USA. • since January 1998

  8. Folate Contents of Foods

  9. Bioavailability • Unstable to oxidation • Bio-availability of folates is variable among foods (30-80%) compared with folic acid. • Bioavailability of Food Folate • ~50% • Bioavailability of Folic Acid • > 90% • They are related to: • Type of diet: conjugase inhibitors • Folate vitamers • Nutritional status: Iron and vitamin C

  10. Biologic Availability to Humans of Folates in Food

  11. Inhibition of Jejunal Folate Conjugase Activities in Vitro by Components of Selected Foods

  12. Digestion • Dietary folates are absorbed as folic acid, 5-methyl-THF and 5-formyl-THF • Polyglutamate must be reduced to mono or di-glutamate forms for absorption. • Conjugases • Brush border conjugase is zinc dependent • Zinc deficiency can diminish folate absorption • Chronic alcohol ingestion can diminish absorption • Conjugase inhibitors in foods can also decrease digestion • pH sensitive

  13. Absorption • Transport System • Carrier mediated (low concentration) • Saturable, energy and sodium dependent. Affected by pH (5.5-6.0) and glucose. • Simple diffusion • Occurs at very high amounts • Inside intestinal cell • Folate reduced to THF • Occurs via NADPH dependent dihydrofolate reductase • Four additional hydrogens added at positions 5, 6, 7, 8 • THF methylated or formylated

  14. Transport • Free in plasma: monoglutamate derivatives, mainly tetrahydrofolic acid (THF). • Taken by liver and converted to 5-methyl-THF and 10-formyl-THF (tightly regulated) • Blood • Folate is found as monoglutamate • Primarily N5-methyl-THF • 2/3 bound to protein; 1/3 free

  15. Absorption and transport of dietary folate Intestinal Lumen conjugase Dietary folate Enterocytes (monoglutamate form) (Predominantly as polyglutamate) (jejunum) Enterohepatic circulation Faeces Plasma Bile (predominantly as 5-CH3FH4) Liver Systemic Circulation Kidney Urine Peripheral Tissues

  16. Folate • Liver/Tissue • Demethylation • Elongation of glutamate tail • pteroylpolyglutamate synthetase (PPS) • Traps folate inside cell • Allows production of other forms • Cell take up monoglutamate derivatives only by two specific processes: • Carrier mediated process requiring energy and Na. (folate binding proteins) • Reduced folate carrier anion-exchange system

  17. Folate • Liver • 33% THF, 37% 5-methyl-THF; 23% 10-formyl-THF, 7% 5-formyl-THF • Most of 5-methyl-THF and 10-formyl-THF is excreted into the bile • Reabsorbed via enterohepatic circulation • Accounts for ~50% of folate that reaches peripheral tissues

  18. Tissue distribution • Total body content: • 5-10 mg (50% in liver) • In tissues with: • Rapid cell division: Low 5-methyl-THF and high 10-formyl-THF • Low cell division: 5-methyl-THF dominates • Folate mainly in mitochondria (10-formyl-THF) and cytosol (5-methyl-THF) • Stored as polyglutamates

  19. Metabolism • Ring reduction: 7,8 dihyrofolate reductase • Side chain reactions: mono-glutamate are converted to poly-glutamate (storage) using polyglutamate synthetase. • Acquisition of single carbon units • Excretion: about 1% of total store • Urine (1-12ug/day) • Feces

  20. Reduction of folate ( R= p-aminobenzoyl glutamic acid) NADP-H+ NADP NADP-H+ NADP Folate7,8-dihydrofolate 5,6,7,8-tetrahydrofolate dihydrofolate tetrahydrofolate reductase reductase

  21. Metabolic functions • Coenzyme in single carbon metabolism • Amino acid metabolism • Serine-glycine interconversion and metabolism • Homocysteine methylation and methionine synthesis • Histidine catabolism • Nucleotide metabolism • Thymidylate synthesis • Purine synthesis • Disposal of one-carbon units • Mitochondrial protein synthesis

  22. Role of folate in single-carbon metabolism. folic acid NADPH NADP NADPH FH4-polyglutamates NADP GLU ADP+Pi ATP formate homoCYS MET ATP ADP+Pi B12 5-methyl-FH4 SER10-formyl-FH4 NADPHFAD GLYdTMPFIGLU formyl GLU NADPFADH2dUMPGLU GLU 5,10-methyl-FH4 5-formyl-FH4 NADP NADPH dTMP 5,10-methenyl-FH4 5-formimino-FH4 NH3 ADP+Pi ATP DNA purines H20 FH2 FH4

  23. Coenzyme in single carbon metabolism • THF accepts one-carbon groups from various degradative reactions in amino acid metabolism • THF then serves as donors of one-carbon units in a variety of synthetic reactions • One-carbon group is bonded to its N5 or N10 atoms or both.

  24. Coenzyme in single carbon metabolism • Folate Co-enzymes • 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) most oxidized

  25. Metabolic Roles of Folate

  26. Metabolic Roles of Folate

  27. FOLATE FUNCTIONS FOLIC ACID SAM dTMP DHF Met Hcy dUMP Purines 5-CH3-THF THF Ser AICAR GAR Gly 5-NH=CH-THF 5,10-CH2-THF 10-HCO-THF 5,10-CH=THF

  28. Amino Acid Metabolism • Serine-glycine interconversion and metabolism • Reversible: Catalyzed by serine hydroxy-methyltransferase (PLP) • Glycine and 5, 10,-methylene THF synthesis • Requires THF and serine • Favored reaction • Serine and THF synthesis • Requires glycine and 5, 10-methylene THF • Methionine regeneration • Requires 5-methyl-THF, homocysteine and B12

  29. Amino Acid Metabolism • Histidine Metabolism Histidine Requires THF Urocanic Acid This reaction used to assess folate status. Give histidine load and measure FIGLU excretion in urine FIGLU THF 5-formimino THF Glutamate

  30. Nucleotide metabolism • Folate is essential for cell division • Pyrimidine (Thymidylate synthesis) • 5,10-methylene THF + dUMP  dTMP + DHF • Catalyzed by thymidylate synthase • 5-fluoro-deoxyuridyte used by the enzyme and forms covalent complex between enzyme and folate (anti-cancer) • DHF + NADPH + H+  THF + NADP+ • Catalyzed by DHF reductase • Methotrexate inhibits DHF reductase • Stops cancer cells from dividing.

  31. O C HN CH CH C O N 5,10-methylene FH4 Ribose-5-P Thymidylate synthetase FH2 reductase FH2 O C CH3 HN C CH C O N D-Ribose-5-P The role of folate in the biosynthesis of thymidylate Deoxyribose uridine monophosphate (dUMP) NADP NADPH.H+ Deoxythymidine monophosphate (dTMP) (Thymidylate)

  32. Nucleotide metabolism • Purine Synthesis • C8 & C2 of purine atoms derived from 10-formyl-THF. • 10-formyl-THF + GAR  THF + formyl-GAR • Catalysed by GART • 10-formyl-THF + AICAR  THF + formyl-AICAR • Catalyzed by AICART • 10-formyl sources: • Oxidation of 5,10-methylene-THF • Direct formylation of THF

  33. Metabolic functions • Disposal of one-carbon units • 10-formyl-THF + NADP++ H2O  THF + CO2 + NADPH + H+ • Catalysed by 10-formy-THF dehdrogenase: • Controlled by 10-formyl-THF:THF ratio • Mitochondrial protein syntesis • Initiation by N-formyl-methionyl-tRNAfmet • 10-formyl-THF + methionyl-tRNAfmet  THF + N-formyl-methionyl-tRNAfmet • Catalysed by methionyl-tRNA transformylase • Essential for bacteria • Mammals: not clear

  34. HOMOCYSTEINE(HCY) _ COO + CH2 CHNH3 CH2 SH • Sulfur containing amino acid • Formed in the methionine cycle • Methionine is essential amino acid obtained • from the diet.

  35. HCY METABOLISM R PPi+Pi S-Adenosyl Methionine (SAM) R-CH3 ATP 2 1 DMG S-Adenosyl Homocysteine Diet Methionine 5 Betaine H2O 4 3 THF B12 Homocysteine B6 Ado 8 6 N5-CH3-THF Cystathionine 9 7 B6 N5,510-CH2-THF Cysteine

  36. Cobalamin N5 methyl THF Methionine ATP Methionine adenosyl transferase Pi + PPi Methionine Synthetase or Homocysteine methyl transferase S-adenosylmethionine (SAM) N5 N10 methylene THF Acceptor of methyl group CH3 acceptor S-adenosyl homocysteine (SAH) H2O Adenosine THF Methyl Cobalamin Homocysteine Resynthesis of methionine: Roles of folate and vitamin B12

  37. Interrelationship of vitamin B12,folate and methionine. 5-CH3FH4 Homocysteine VitaminB12 Methionine C1 FH4 5,10-CH2-FH4 FH2 10-CHO- FH4 deoxyuridine deoxythymidine monophosphate monophosphate 5-10-CH2-FH4

  38. HCY REGULATION R PPi+Pi S-Adenosyl Methionine (SAM) R-CH3 ATP DMG S-Adenosyl Homocysteine Diet Methionine Betaine H2O THF B12 Homocysteine B6 Ado SAM N5-CH3-THF Cystathionine SAM B6 N5,510-CH2-THF Cysteine

  39. GENETIC DEFECTS R PPi+Pi S-Adenosyl Methionine (SAM) R-CH3 ATP DMG S-Adenosyl Homocysteine Diet Methionine Betaine H2O THF B12 Homocysteine Ado B6 N5-CH3-THF Cystathionine B6 N5,510-CH2-THF Cysteine

  40. HCY AND HEART DISEASE • 1st identified in individuals with an enzymatic defect (CBS) • Homocystinuria • Developed atherosclerosis, stroke and MI at early age • Retrospective and prospective studies have suggested that moderately elevated blood HCY level is an independent risk factor • CONTINUOUS & GRADED relationship

  41. HCY AND HEART DISEASE • Boushey et al. 1995 • Meta-analysis including 17 studies • Relative increase in risk of CHD (Odds Ratio) for a 5 mmol/L increment in Hcy • ~1.7 (70% increased risk) • Odds ratio for stroke (men and women) • 1.9 (90% increased risk) • Odds ratio for Peripheral vascular disease • 2.0 (100% increased risk or twice as likely)

  42. HCY CONCENTRATION

  43. LOWERING HCY • Folate (Substrate) • Up to 400 ug/d (plateau with > intakes) • Defect in MS and inadequate folate stores • Vitamin B12 (Co-enzyme) • Only if deficiency exists • Vitamin B6 (Co-enzyme) • After methionine load • Betaine (Defect in MS) • Choline

  44. FACTORS AFFECTING HCY • Genetic Defects • Cystathionine-b-synthase deficiency • Impaired methionine synthase activity • 5,10-methylene-THF reductase deficiency • Nutritional • Folate, vitamin B12 or vitamin B6 deficiency • Renal Disease • Malabsorption syndromes • Drug interactions

  45. FACTORS AFFECTING HCY • Age • Gender • Lower in females (8 vs. 10 mmol/L) • Fasting Hcy level increases after menopause • Lower during pregnancy and during ERT • Smoking • Increase Hcy

  46. Potential Mechanisms • Autoxidation of Hcy • Generates H2O2 and free radicals • Enhances procoagulant activity • Inhibits anticoagulant activity • Reacts with NO, which inhibits NO production • Stimulates smooth muscle cells (proliferation) • Oxidization of LDL

  47. Folate • Interrelationships with Other Nutrients • Vitamin C protective against folate oxidation • Folate may interfere with zinc absorption • Tight relationship between vitamin B12 and folate • Methyl Trap Hypothesis • Vitamin B12 deficiency traps folate in its 5-methyl-THF form • THF is NOT regenerated • Decreased production of other folate enzymes including 5,10-methylene-THF required for thymidine synthesis

  48. Folate • Metabolism and Excretion • Under normal circumstances, body holds onto folate tenaciously. • Folate reabsorbed by kidney and enterohepatic circulation • Very little urinary excretion of intact folate • Feces contains folate made by gut bacteria • Catabolism • Occurs between C9 and N10 • pABG and apABG produced and excreted in urine

  49. Deficiency effects • Megaloblastic anemia • Cancer • Folate antagonists • Preganacy and birth defects • Drugs

  50. Megaloblastic anemia • Megaloblastic changes in other tissues • Cellular DNA content increased (strand breaks) • Uracil misincorporation to DNA (replace thymidylate) • Pernicious anemia (B12 deficiency) identical to folate deficiency • 5-CH3-THF poor substrate for folypolyglutamate synthetase • Nitrous oxide: methionine synthase deficiency: folate deficiency

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