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Folate and b12 metabolism


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a basic introduction to folate and b12 metabolism

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Folate and b12 metabolism

  1. 1. Folate and B12 metabolism Dr JG Nel Department of Haematology and Cell Biology 5 June 2008
  2. 2. Folate and Vitamin B12  History  Chemical characteristics  Sources  Absorption  Transport in the body
  3. 3. Folate and Vitamin B12  Stores and requirements  Cobalamin and Folate in cellular metabolism
  4. 4. Vitamin B12
  5. 5. The History of Vitamin B12  George Whipple showed that beef liver improved the formation of red corpuscles in anaemic dogs.  1926: Minot and Murphy announced that a daily diet of a pound of liver can control pernicious anaemia.  1930s: antipernicious factor- B12 named before it was isolated.  1948: Bacterial assay for the determination of B12 developed by Karl Folkers  Vitamin B12 Isolated by two groups at the same time
  6. 6. The History of Vitamin B12  1956: Dorothy Hodgkin determines B12 structure using X-ray crystallography.  1971: Robert B. Woodward synthesizes B12
  7. 7. Chemical characteristics of Vitamin B12  Three primary domains 1. Corrin nucleus 2. Nucleotide  B group linked to Co 1. CN 2. OH 3. CH3* 4. Adenosyl*
  8. 8. Chemical characteristics of Vitamin B12  Product of bacterial biosynthesis  Not destroyed by heat  Mol. Mass : 1355.37g/mol  Metabolism : hepatic  Excretion : renal  Half life : 6 days, 400 days in liver
  9. 9. Sources of Vitamin B12  Foods of animal origin  Milk  Meat –esp liver and shellfish  eggs  Unwashed plants  Fortified food products eg. cereals  Cyanocobalamin supplements –oral, intranasal and IM
  10. 10. Vitamin B12 Absorption Two mechanisms 1. Passive 2. Active
  11. 11. Vitamin B12 Absorption Passive absorption  mucosal surfaces  rapid  inefficient (less than 1% of oral dose)
  12. 12. Vitamin B12 Absorption Intrinsic factor  Produced by parietal cells in fundus and body of stomach  Nucleotide portion of Co fits into a pit on the surface of the protein  Does not bind pseudocoabalamin compounds
  13. 13. Vitamin B12 Absorption Active  Localised to ileum in humans  Efficient for small oral doses of cobalamin  Normal mechanism by which the body acquires cobalamin
  14. 14. Vitamin B12 Absorption  B12 freed from non-specific binding to dietary protein by peptic digestion  Rapidly binds to pepsin- resistant high affinity R- protein  Duodenum R-protein degraded by pancreatic trypsin  IF binds exogenous cobalamin and endogenous cobalamin from bile by it’s C-terminal
  15. 15. Vitamin B12 Absorption  In terminal ileum IF- cobalamin binds to Cubilin and enters the cell via receptor mediated endocytosis  Cobalamin dissociates from IF and binds to Transcoballamin  IF is degraded  Cobalamin transported into the portal circulation after 6 hours.  Limited receptor sites
  16. 16. Enterohepatic Circulation of Vitamin B12  0.5ug-5ug enters bile each day  Binds to IF and a portion gets reabsorbed with Cobalamin derived from sloughed intestinal cells
  17. 17. Transport of Vitamin B12  Transported mainly by two proteins  Haptocorrin (formerly Transcobalamin I) 80%  Transcobalamin (formerly Transcobalamin II) 20%
  18. 18. Transport of Vitamin B12 Haptocorrin  Glycoprotein  Related to other HCs  Derived from specific granules of neutrophils  Bound tighly to Co  Removed from plasma by hepatic glycoprotein receptors
  19. 19. Transport of Vitamin B12 Transcobalamin  B2 globulin  Synthesized by: liver,macrophages,ileum, endothelium  Readily gives up cobalamin  Enters cells via receptor mediated endocytosis
  20. 20. Vitamin B12 Stores  Normal Western Diet 5-30ug Cobalamin daily  Losses (urinary and fecal) 1-3ug (0.1% of body stores)  Requirement 1-3ug daily  Body stores 2-3mg
  21. 21. Folate
  22. 22. The history of Folate  1931 Lucy Wills: dietary yeast prevents anaemia in pregnant women–“Wills factor”  1941 Henry K. Mitchell: isolates folic acid from spinach leaves.  1946 Yellapragada Subbarao synthesized folic acid.  1980s evidence that the addition of folic acid in the diets of pregnant women can prevent birth defects.
  23. 23. Chemical properties of Folic acid  Folate = ionic form of folic acid lacking one H atom  Pteroylmonoglutamic acid  Occurs as poly- and monoglutamic variants  Watersoluble  Destroyed by heat and light exposure
  24. 24. Sources of Folate  Leafy vegetables  Dried beans and peas  Fortified cereal products  Sunflower seeds  Eggs, liver and milk  Yeast
  25. 25. Absorption of Folate  dietary folates ingested as polyglutamates  absorbed as monoglutamate.  Hydrolase in brush border of jejunal and ileal epithelial cells deconjugates the polyglutamate to monoglutamate form.  enters the cell by simple diffusion or by folate binding proteins.
  26. 26. Transport of Folate  Reduced to tetrahydrofolate in mucosal cell  Methylated before release into the portal circulation  Loosely bound to albumin  Methylated THF binds to specific folate receptors and enters the cell via receptor mediated endocytosis.  Released from the receptor, transferred to cobalamin
  27. 27. Transport of Folate  In the cell folate needs to polyglutamated in order to aid retention of the molecule
  28. 28. Folate Stores  Requirement 100- 500ug/day  Hepatic stores 8-20mg  Enterohepatic circulation.  With dietary deprivation stores begin to decline in 3-4 weeks.  RDA 400ug
  29. 29. Vitamin B12 and Folate in Cellular metabolism
  30. 30. Biological role of Vitamin B12 Only two reactions in the body are known to require cobalamin: 1. Methylmalonyl CoA isomerization 2. The methylation of homocysteine to methionine
  31. 31. Biological role of Vitamin B12 Methylmalonyl CoA isomerization Adenosylcobalamin Methylmalonyl CoA Succinyl CoA Methylmalonyl CoA Mutase
  32. 32. Biological role of Vitamin B12 The methylation of homocysteine to methionine • requires  5-Methyltetrahydrofolate as methyldonor  Methylcobalamin as coenzyme • Irreversable • 1st step in the conversion Methyltetrahydrofolate intracellular folate Coenzymes
  33. 33. Biological role of Folate  Purine synthesis DNA,RNA  Pyrimidine synthesis DNA  Amino acid interconversion  Serine-Glycine  Homocysteiene to Methionine  Forminoglutamic acid to glutamic acid