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Vitamin

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Vitamin

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Vitamin

  1. 1. Trao đổi trực tuyến tại: http://www.mientayvn.com/Y_online.html
  2. 2. Reading material • Principles of Biochemistry with a Human Focus by Garrett and Grisham, First Edition, 2002, pages 453-468 • Handbook of NonPrescriptions Drugs, 11th edition, Chapter entitled “Nutritional Products” by Loyd V. Allen, Jr.
  3. 3. Vitamins • a group of organic compounds needed in small quantities in the diet for normal activity of tissues • between 14 – 20 substances have been identified as vitamins • many vitamins act as cofactors, coenzymes or prosthetic groups for enzymes • most vitamins are derived from diet • no calories are derived from vitamins
  4. 4. Vitamins • first vitamin discovered was thiamine or B1 • the term vitamin is derived from the fact that the substances are needed for life (vita) and because thiamine happened to be an amine the term was coined as such • however, not all vitamins are amines or nitrogen containing compounds
  5. 5. Vitamins • vitamin requirements are usually expressed as RDA’s (recommended dietary allowances) • guidelines are provided by 2 organizations: • the Food and Nutrition Board of the National Academy of Sciences- National Research Council • the Food and Drug Administration (FDA)
  6. 6. RDAs • applications of RDAs include: • evaluating the adequacy of the national food supply • establishing standards for menu planning • establishing nutritional policy for public institutions/organizations and hospitals • evaluating diets in food consumption studies • establishing labeling regulations • setting guidelines for food product formulation • developing materials for nutritional education
  7. 7. RDAs • RDAs have limitations: • they are too complex for direct consumer use • they do not state ideal or optimal levels of intake • the allowances for some categories are based on limited data • the data on some nutrients in foods is limited • they do not evaluate nutritional status • they do not apply to seriously ill or malnourished patients
  8. 8. Vitamin deficiencies • primary food deficiency • crop failure • food storage loss • food preparation loss • diminished food intake • poverty • anorexia • food fadism • chronic diseases
  9. 9. Vitamin deficiencies • diminished absorption • absorption defect • parasites • malignancies • increased requirements • rapid growth • increased physical activity • pregnancy • hyperthyroidism • increased loss • drug therapy • diuresis • lactation
  10. 10. Vitamin loss Loss is seen mainly in storage or food preparation • Vitamin A: sensitive to oxygen and light • Vitamin D: usually little loss • Vitamin E: sensitive to oxidation especially when heated or with alkali • Vitamin K: sensitive to acids, alkali, light and oxidizing agents • Vitamin C: very sensitive to oxidation, especially when heated in contact with metals • Vitamin B complex: water solubility results in loss in cooking water • Riboflavin is sensitive to light
  11. 11. Vitamins • Vitamins are typically divided into 2 groups: – The fat soluble vitamins • A, D, E, and K – The water soluble vitamins • The B vitamins (B1, B2, B3, B6, B7, B12 and pantothenic acid) • Ascorbic acid (vitamin C)
  12. 12. Bogus vitamins • Vitamin B4 adenine • Vitamin B10 identical with folic acid • Vitamin B11 “ “ “ “ • Vitamin B15 pangamic acid • Vitamin B13 orotic acid • Vitamin B17 laetrile • Vitamin B19 wormser’s secret formula
  13. 13. Cofactors • provide “chemical teeth” for enzymes • sometimes referred to as coenzymes • enzymes: proteins with catalytic activity – simple enzymes: large protein (polypeptide) that catalyzes a reaction. The enzyme gets all the “tools” (chemical teeth) it needs from the amino acids. However, there are only 20 different amino acids – conjugated enzymes : apoenzyme + cofactor = holoenzyme
  14. 14. EXAMPLE:Proteases: enzymes that cleave peptide bonds N N N H R O H R' O H N OH H R O + H2N N R' O H H2O protease Enzymes perform catalytic reactions such as hydrolysis; the side chains of amino acids participate in the reactions
  15. 15. CH2OH CH2 N H N CH2-COOH all these tools come from amino acids in the protein active site Usually electron-rich side chains are involved in the catalysis Aliphatic chains are normally involved in hydrophobic interactions example of a simple enzyme A serine protease enzyme such as chymotrypsin
  16. 16. COO- O HN N H ASP HIS SER COOH O- N NH ASP HIS SER R N H O R' COOH O N NH ASP HIS SER HN O- R R' COO- O HN N ASP HIS SER R O R' NH2 H2O HYDROLYTIC CATALYSIS
  17. 17. Example of a conjugated enzyme N N R O H H N R' O Zn+2 OH cofactor needed for reaction PRODUCTS + ENZYME Zinc protease such as ACE
  18. 18. Cofactors • all water-soluble vitamins with the exception of vitamin C are converted/activated to cofactors • only vitamin K of the fat-soluble vitamins is converted to a cofactor • not all vitamins are cofactors; i.e., lipoic acid is not a vitamin • cofactors may also act as carriers of specific functional groups such as methyl groups and acyl groups
  19. 19. The water soluble vitamins
  20. 20. Pantothenic acid (vitamin B5) CH2HO C CH3 CH3 CH OH C N O CH2 H CH2 COOH First recognized in 1933 as a growth factor for yeast (Roger J. Williams)
  21. 21. Pantothenic acid • a yellow viscous oil (free acid) • stable to moist heat (not to dry heat) and to oxidizing and reducing agents • hydrolyzed in acid or alkaline medium • sources (numerous): liver, kidney, eggs, lean beef, milk, molasses, cabbage, cauliflower, broccoli, peanuts, sweet potatoes, kale (derive its name from everywhere)
  22. 22. Pantothenic acid • serves in its activated form as the cofactor for coenzyme A (CoA) and the acyl carrier protein (ACP) • first phosphorylated by ATP to 4’- phosphopantothenate • next is the formation of 4’-phosphopantetheine by addition of cysteine and decarboxylation • adenylation by ATP forms dephospho-CoA • phosphorylation to the 3’-OH of the ribose generates CoA (coenzyme A)
  23. 23. HH OPO3 OH H H O N N N N H2C O PO O O- PO O- O N OH N O H N O H SH NH2 Coenzyme A N S CH3 O O H Acetyl CoA
  24. 24. Coenzyme A • performs a vital role by transporting acetyl groups from one substrate to another • the key to this action is the reactive thioester bond in the acetyl form of CoA • the thioester bond is stable enough that it can survive inside the cell, but unstable enough that acetyl-CoA can readily transfer the acetyl group to another molecule
  25. 25. N CH3 H3C H3C OH N CH3 H3C H3C O CH3 O acetyl CoA CoA acetylcholinecholine Example of an acetylation reaction Acetylcholine is an important neurotransmitter in the autonomic nervous system (cholinergic) and in the brain
  26. 26. Pantothenic acid • Deficiency: – rats • graying of hair/fur in black rats • dermatitis • inflammation of nasal mucosa • hemorrhage of adrenal cortex – humans • has not been encountered or extremely rare • difficult to induce with either synthetic diets and/or with antagonists (omega- methylpantothenic acid
  27. 27. Pantothenic acid • vague symptoms in human deficiency: • numbness and tingling in feet “burning foot” • fatigue • GIT disturbances • available pharmaceutically as calcium pantothenate (d-isomer) and as racemic mixture • 5 - 7 mg/day appear to prevent signs of deficiency • appears to be non-toxic (up to 10-20 gm have been tolerated)
  28. 28. Thiamine N N NH2 H3C CH2 N S H3C CH2-CH2-OH THIAMINE Vitamin B1; antiberi-beri vitamin; antineuritic factor was the first water soluble vitamin discovered (Eijkman)
  29. 29. Thiamine • has the odor and flavor of yeast • slowly destroyed by moist heat; more rapidly destroyed in a basic medium than in an acid one • source: whole cereals and grains; yeast; organ meat • pharmaceutical products use the hydrochloride or mononitrate salts
  30. 30. Thiamine • active form is thiamine pyrophosphate (formed by the action of thiamine diphosphotransferase) • involved in the oxidative decarboxylation of pyruvic acid and α-ketoglutaric acid • involved in the transketolase reactions of the triose phosphate pathway • also required for nerve function (unrelated to coenzyme activity)
  31. 31. Conversion of thiamine to TPP
  32. 32. Typical reactions catalyzed by TPP
  33. 33. Reactions in which thiamine pyrophosphate is a cofactor • Pyruvate decarboxylase • Alcohol fermentation – pyruvate to acetaldehyde • Pyruvate dehydrogenase • Synthesis of acetyl-CoA • Alpha-ketoglutarate dehydrogenase • Citric acid cycle • Transketolase reaction • Carbon-fixation reactions of photosynthesis • Acetolactase synthetase • Valine, leucine biosynthesis
  34. 34. Thiamine pyrophosphate • the key portion of this cofactor is the thiazolium ring with its acidic hydrogen • the hydrogen is removed by the enzyme forming an ylid (anion next to cation) • the anion can then react with carbonyl groups in such molecules as pyruvate • the pyrophosphate functionality acts as a chemical handle which holds the cofactor in place within the enzyme
  35. 35. N N NH2 N S C H3C H H2C H2 C O P H3C O O O- P O- O O- thiazolium ring thiamine pyrophosphate N N NH2 N S C H3C C H2C H2 C O P H3C O O O- P O- O O- OH H3C H Hydroxyethyl thiamine pyrophosphate
  36. 36. N S CH3 H Cl N S CH3 Cl acidic hydrogen H O O O- pyruvate N S CH3 Cl HO O-O N S CH3 Cl OH - CO2 N S CH3 N S CH3 Cl OH resonance ylid H O H H3C H O + ylid H+ acetaldehyde Chemical mechanism for action of B1 in pyruvate dehydrogenase
  37. 37. C CH2OH C O HO H CH OH CH2-OPO3H2 C CH OH CH OH CH2-OPO3H2 C OH OHH D-xylulose-5-phosphate D-ribose-5-phosphate C C OH CH OH CH2-OPO3H2 H OH C H HHO C CH2OH O C C OHH OH CH2-OPO3H2 + septulose-7-phosphate 3-phosphoglyceraldehy transketolase TPP Transketolase reaction
  38. 38. Transketolase reaction C CH2OH C O HO H CH OH CH2-OPO3H2 D-xylulose-5-phosphate D-erythrose-4-phosphate C C OHH OH CH2-OPO3H2 + 3-phosphoglyceraldehyde transketolase TPP C CH OH C OH OHH CH2-OPO3H2 CH OH C HHO C CH2OH O CH OH CH2-OPO3H2 D-fructose-6-phosphate These reactions provide a link between the pentose phosphate pathway and glycolysis Activity of erythrocyte transketolase is commonly used as an index of thiamine deficiency
  39. 39. Thiamine deficiency • earliest symptoms of thiamine deficiency include: – constipation – appetite suppression – nausea – mental depression – peripheral neuropathy – fatigue
  40. 40. Thiamine deficiency (severe) • beri-beri (once associated with white polished rice diets and with highly milled wheat diets) • 2 clinical types • dry beri beri or neuritic beriberi – associated with polyneuropathy (depressed peripheral nerve function, sensory disturbance, loss of reflexes and motor control and muscle wasting • wet beri beri or cardiovacular beriberi – edema, congestive heart failure
  41. 41. N N N S OH H3C H3C CH2-CH2-OH OXYTHIAMINE NH2 H3C N H3C CH2-CH2-OH NEOPYRITHIAMINE These 2 compounds are potent antithiamine agents which may be used to induce symptoms of vitamin B1 deficiency in selected animals. Oxythiamine competitively inhibits thiamine pyrophosphate and becomes active after phosphorylation; neopyrithiamine prevents the conversion of thiamine to thiamine pyrophosphate
  42. 42. Other clinical applications • Alcohol neuritis (peripheral neuropathy) • Sharp burning pain in the feet • Deep muscle tenderness with numbness • Coarse tremors, foot drop • Wernicke’s encephalopathy • Results from degeneration of basal ganglia due to chronic/heavy use of alcohol • Rigidity of extremities • Complete or partial ophthalmoplegia • Sleep disturbances • Nausea and vomiting
  43. 43. Other clinical applications • Korsakoff’s syndrome or psychosis • Also a complication of chronic/heavy use of alcohol • Usually follows DT’s (delirium tremens) • Memory loss • Delusions • Disorientation • Ocular palsies • Combined Wenicke-Korsakoff syndrome • Pregnancy neuritis • Certain gastrointestinal disorders
  44. 44. Requirement for thiamine • Based on energy needs – 0.3 – 0.6 mg/1000 calories – Increased requirements: • Pregnancy and lactation • Eating large amounts of raw sea food (clams) – contain thiaminase • Stress situations (high level of exercise, fever, hyperthyroidism) • Drinking large quantities of tea (contains antagonist)
  45. 45. Thiamine assay • biologic assay – in animals – time consuming and costly (curative or protective) • microbiologic using bacteria which require thiamine for growth • chemical/fluorescent assay – conversion of thiamine to thiochrome by alkaline ferricyanide N N N N SH3C CH 2-CH 2-OH CH 3 THIOCHROME
  46. 46. Lipoic acid • lipoic acid is a co-factor found in pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, two multienzymes involved in α-keto acid oxidation • lipoic acid functions to couple acyl group transfer and electron transfer during oxidation and decarboxylation of α-ketoacids • no evidence exists of a dietary lipoic acid requirement in humans; therefore it is not considered a vitamin
  47. 47. S S H2C C H2 CH COOH SH HS H2C C H2 CH COOH S S H2C C H2 CH C N O H CH NH C O lipoic acid, oxidized form lipoic acid, reduced form lipoamide complex (lipoyl-lysine conjugate) Lipoic acid exists in 2 forms: a closed-ring disulfide form and an open-chain reduced form; oxidation-reduction cycles interconvert these 2 species; lipoic acid exists covalently attached in an amide linkage with lysine residues on enzymes
  48. 48. Riboflavin • vitamin B2, lactoflavin (ovo, hepato, verdo), vitamin G • a heterocyclic flavin linked to ribose analogous to the nucleosides in RNA • orange-yellow fluorescent compound • found in significant quantities in green leafy vegetables, milk and meats • heat stable, but easily destroyed by light • recommended intake is related to energy intake (kcal) – RDA 1 – 2 mg/day
  49. 49. N N N NH3C H3C O C O H C HH C H OH C H2C H OH H OH OH RIBOFLAVIN dimethylisoalloxazine ring system – confers some degree of planarity to the molecule and also color (yellow)
  50. 50. N N N NH3C H3C CH3 O H O LUMIFLAVIN (produced by photochemical cleavage of riboflavin under alkaline conditions) N NH3C H3C CH3 O COOH + UREA NHCH3 NH2H3C H3C OH- OH- NH N OO O O H alloxan 4-amino-1,2-dimethyl 5-methylaminobenzene Decomposition of riboflavin
  51. 51. Riboflavin • 2 cofactors are involved: – riboflavin phosphate (flavin mononucleotide, FMN) – flavin adenine dinucleotide (FAD) • involved in the metabolism of carbohydrates, fats and proteins (flavin dehydrogenases/flavoproteins) • hydrogen carriers in the respiratory chain
  52. 52. N N N N O O H H3C H3C H2C C C C C O H OH H OH H OH H H P O OH O P O O OH CH2 O N N N N NH2 OH OH H H HH FLAVINE ADENINE DINUCLEOTIDE
  53. 53. reduced substance oxidized substance FAD FADH2 cytochrome electron system (electron transport chain) dehydrogenases Riboflavin
  54. 54. Riboflavin N N N N O H O H3C H3C N N N N O H O H3C H3C H H FAD (oxidized form) FADH2 (reduced form) hydrogen addition occurs in 2 steps
  55. 55. Riboflavin • Enzymes utilizing riboflavin cofactors: – NADH dehydrogenase – succinate dehydrogenase – d and l-amino acid oxidases – pyridoxine-5-phosphate oxidase – glutathione reductase – xanthine oxidase • In some enzymes, the cofactor is covalently bonded to an amino acid (dehydrogenases)
  56. 56. Dehydrogenase reaction CH2 CO2- CH2 CO2- FAD FADH2 succinate dehydrogenase C CO2- C CO2- H H succinate fumarate
  57. 57. Amino acid oxidases C R NH3+H CO2- H2O NH3 FMN FMNH2 R C O CO2- most amino acids (except serine, threonine, basic, and dicarboxylic acids) can be deaminated by L-amino acid oxidases
  58. 58. Xanthine oxidase N N N N OH H N N N N OH H HO N N N N OH H HO OH hypoxanthine xanthine uric acid xanthine oxidase Xanthine oxidase is a flavoprotein which also contains Fe and Mo
  59. 59. Fatty acyl-CoA desaturase H H R H SCoA O R H SCoA O H FAD FADH2 fatty acyl-CoA desaturase Important step in the biosynthesis of unsaturated fats; this reaction is actually more complex than shown here and involves other cofactors, but FAD is a key cofactor for the enzyme
  60. 60. Riboflavin deficiency • seldom seen in industrialized societies • deficiency when seen: • cheilosis (vertical fissure in the lips) • angular stomatitis (craks in the corner of the mouth) • glossitis • photophobia • seborrheic dermatitis • normochromic normocytic anemia • usually encountered along with pellagra (niacin deficiency) • newborns treated for hyperbilirubinemia by phototherapy (riboflavin is unstable to light)
  61. 61. Biotin NN S O H H HH (CH2)4-COOH BIOTIN
  62. 62. Biotin • an imidazole sulfur containing compound • sometimes referred to as vitamin B7 or vitamin H • widely distributed in foods (liver, kidney, milk, molasses) • a large portion of the daily need of biotin is met by synthesis by intestinal bacteria • deficiency is usually the result of a defect in utilization rather than simple dietary deficiency
  63. 63. Biotin • like lipoic acid, biotin is converted to its coenzyme form (called biotinyllysine or biocytin) by formation of a covalent amide bond to the nitrogen of a lysine residue • like lipoic acid it performs a highly specialized function : adds a carboxyl group to substrates
  64. 64. Biotin • biochemical role: carbon dioxide fixation • two step process: 1. Binding of CO2 to biotin – N-carboxybiotin 2. Transfer of CO2 to a substrate – Activation of biotin requires enzyme, CO2, ATP and Mg++
  65. 65. Biotin Biotin-dependent enzymes: • Pyruvate carboxylase (synthesis of oxaloacetate for gluconeogenesis and replenishment of the citric acid cycle) • Acetyl CoA carboxylase (fatty acid biosynthesis) • Propionyl-CoA carboxylase β-methylcrotonyl-CoA carboxylase • holocarboxylase synthase (multiple carboxylase)
  66. 66. Reactions involving biotin enzymes CH3C O CO2- CCH2 O CO2--O2C pyruvate oxaloacetate CH3C O SCoA CCH2 O SCoA-O2C acetyl CoA malonyl CoA CCH2 O SCoAH3C propionyl CoA CCH O CO2--O2C CH3 methylmalonyl CoA HCO3 - + NH4 + + ATP CH2N O O P OH OH O carbamyl phosphate
  67. 67. Biotin • deficiency: • quite uncommon • can be induced by feeding raw egg white (avidin) • avidin is a protein which binds tighly with biotin (MW 70,000) • symptoms are: anorexia, nausea, muscle pain, fine scaly desquamation of the skin • requirements: 150 – 200 mcg/day • therapeutic use: in babies with infantile seborrhea (cradle cap) and Leiner’s disease
  68. 68. Pyridoxine (vitamin B6) N CH2OH CH2OHHO H3C PYRIDOXINE A pyridine derivative
  69. 69. N CHO CH2OHHO H3C N CH2NH2 CH2OHHO H3C PYRIDOXAMINEPYRIXOXAL Other forms of B-6 Collectively, pyridoxine, pyridoxal and pyridoxamine are known as vitamin B6
  70. 70. Pyridoxine • vitamin B6, rat “acrodynia factor”, antidermatitis factor • widespread occurrence • pyridoxine: mostly in vegetable products • pyridoxal and pyridoxamine: mostly in animal products • pyridoxine is stable in acid solution, but unstable in neutral or alkaline solutions (destroyed by light)
  71. 71. N HO H3C CH2OH CH2OH pyridoxine N HO H3C CH2OH CHO N HO H3C CH2OH CH2-NH2 pyridoxal pyridoxamine N HO H3C CHO CH2 O P O OH OH N HO H3C CH2-NH2 CH2 O P O OH OH pyridoxal phosphate pyridoxamine phosphate N HO H3C CH2OH COOH pyridoxic acid
  72. 72. Pyridoxal phosphate • pyridoxine is converted to pyridoxal phophate by phosphorylation and oxidation to the aldehyde • pyridoxal phosphate is then attached to the holoenzyme via a covalent bond to a lysine residue (a Schiff’s base) • the Schiff’s base bond is readily broken and reformed • this reversibility is very important in the biochemical action of this cofactor
  73. 73. N H CH2OH CH2OH H3C HO N H CH2OPO3 H3C HO N H CH2OPO3 H3C HO HO HN OH H N Biochemical functions Able to catalyze the breakdown of amino acids
  74. 74. Pyridoxal phosphate Biochemical functions: 1. Decarboxylation of amino acids 2. Transaminase reactions 3. Racemization reactions 4. Aldol cleavage reactions 5. Transulfuration reactions 6. Conversion of tryptophan to niacin 7. Conversion of linoleic acid into arachidonic acid (prostaglandin precursor) 8. Formation of sphingolipids
  75. 75. N H H3C HO HN H Lys N H H3C HO HN H R O- O R CO2H NH2 Lys NH2 N H H3C HO N R H N H H3C HO N R H H N H H3C HO N R H H H H+ N H H3C HO N Lys H H R Lys NH2 H NH2 resonance stabilization - CO2 Decarboxylation of amino acids
  76. 76. Important transaminases • ALT ( alanine aminotransferase) • formerly known as SGPT (serum glutamate pyruvate transaminase) • alanine + alpha-ketoglutarate = pyruvate + glutamate • increased serum level in liver injury
  77. 77. Important transaminases • AST (aspartate aminotransferase) • formerly known as SGOT (serum glutamate oxaloacetate transaminase) • aspartate + alpha-ketoglutarate = oxaloacetate + glutamate • elevated when heart and/or liver are damaged
  78. 78. Important decarboxylases SERINE ETHANOLAMINE ACETYLCHOLINE TYROSINE DOPA DOPAMINE EPINEPHRINE TRYPTOPHAN 5-HT SEROTONIN HISTIDINE HISTAMINE GLUTAMIC ACID GAMMA AMINOBUTYRIC ACID (GABA) CYSTEINE CYSTEINE SULFINIC ACID TAURINE - CO 2 - CO 2 - CO 2 - CO 2 - CO 2 - CO 2
  79. 79. N C N C COO-H R H H N C H N C R COO- aldimine ketimine N H CH2 NH2 COO-C O R alpha-keto acid pyridoxamine phospha Mechanism for transamination reaction
  80. 80. Pyridoxine • deficiency: – difficult to produce in humans – may be accomplished artificially with a pyridoxine antagonist (deoxypyridoxine) – symptoms include: nausea and vomiting, seborrheic dermatitis, depression and confusion, mucous membrane lesions, peripheral neuritis, anemia
  81. 81. Pyridoxine antagonists N N NH-NH 2 Hydralazine (antihypertensive) N C O NH NH2 isoniazid (antitubercular) O N OH2N H cycloserine (antitubercular) CC CH3 H COOHHS CH3 NH2 penicillamine (antirheumatic; Wilson's disease)
  82. 82. Pyridoxine can antagonize the antiparkinsonian use of L-DOPA L-DOPA L-DOPA L-dopamine L-dopamine CO 2 Brain B 6 stimulates this reaction outside of the brain use carbidopa: an inhibitor of DOPA decarboxylase in combination with DOPA: Sinemet 10/100 or Sinemet 25/250
  83. 83. Pyridoxine deficiency • can be monitored by measuring the level of xanthurenic acid in the urine • this is related to a decrease in kynureninase activity (pyridoxal phosphate is the coenzyme) • kynurenine, a breakdown product of tryptophan is normally converted to kynurenic acid – but in B6 deficiency it is shunted to form xanthurenic acid
  84. 84. XANTHURENIC ACID N COOH OH OH
  85. 85. Pyridoxine • requirements: • children: 0.5 – 1.2 mg • adults: 2.0 mg • pregnancy: 2.5 mg – Requirement for B6 is proportional to the level of protein consumption • therapeutic uses: • deficiency • to counterract the effects of antagonists • certain rare forms of anemia • in women taking oral contraceptives (estrogen shifts tryptophan metabolism
  86. 86. N COOH NICOTINIC ACID N CONH 2 NICOTINAMIDE Discovered in 1913 from yeast; also known as vitamin B3 1915 – 1920: Irving Golberg demonstrated that lack of niacin causes pellagra one of the simplest vitamin; like B6 also a pyridine derivative
  87. 87. Oxidation of nicotine yields nicotinic acid N N H N COOH[OXIDATION] HNO3 nicotine nicotinic acid This reaction does not occur in vivo – strictly a laboratory reaction
  88. 88. Nicotinic acid • niacin, vitamin B3, niacinamide, antipellagra vitamin • both form are active: the free acid and the amide • sources: organ meat (largest source), fish, yeast, dried fruit, nuts, cereal grains, some vegetables • pellagra-inducing diets: corn meal, corn starch, sweet potatoes, rice, syrup, pork fat (once a common diet in southern states among sharecroppers)
  89. 89. H H2C H OH OH H H O N NH2 O H O P O O O- P O O- O CH2 HH OH OR H H O N N N N NH2 NAD - OXIDATION REACTIONS R = H NADPH - REDUCTION REACTIONS R = PO3 Coenzyme forms Two cofactor forms of niacin: NAD and NADP; these cofactors are not tightly held by the enzyme and may be reused for reaction after reaction
  90. 90. Biochemical function N C NH2 O N C NH2 OHH NAD + or NADP + + H + NADH + H + or NADPH + H + In the older literature NAD+ is referred to as DPN or coenzyme I NADP+ is referred to as TPN or coenzyme II
  91. 91. Oxidized and reduced forms
  92. 92. Sparing action of tryptophan TRYPTOPHAN FORMYLKYNURENINE KYNURENINE 3-HYDROXYKYNURENINE3-HYDROXYANTHRANILIC ACID NICOTINIC ACID B6-dependent reaction Tryptophan can substitute for niacin: 60 mg of tryptophan is equivalent to 1 mg of niacin; 60 gm of protein contains 600 mg of tryptophan which then represent 10 mg of niacin
  93. 93. CH COOH NH 2 N H CH 2 CH 2 O CH COOH NH 2 N H C O Htryptophan N-formylkynurenine CH 2 O CH COOH NH 2 NH 2 CH 2 O CH COOH NH 2 NH 2 OH 3-hydroxykynurenine kynurenine alanine COOH NH 2 OH CO 2 N COOH 3-hydroxyanthranilic acid blocked by deficiency of thiamine blocked by deficiency of riboflavin blocked by deficiency of pyridoxine
  94. 94. Pellagra • Early stages: • Anorexia • Indigestion • Muscle weakness • Reddened skin • Rough skin • Advanced stages • 3 D’s of pellagra: dermatitis, diarrhea, dementia
  95. 95. Clinical uses of nicotinic acid • pellagra symptoms from: • gastric ulcer or carcinoma • diarrhea • isoniazid therapy • carcinoid syndrome • Hartnup disease (impairment of tryptophan absorption) • peripheral vasodilator (nicotinic acid or nicotinyl alcohol) • hypolipidemic agent (only nicotinic acid in large doses – lowers both triglycerides and cholesterol (Niaspan, Nicobid)
  96. 96. Carcinoid syndrome • a slow growing neoplasm of enterochromaffin cells (ileum, stomach, bronchus) • tryptophan metabolism is altered resulting in excess serotonin synthesis • symptoms include: • facial flushing • edema of head and neck • abdomina cramps and diarrhea • asthmatic symptoms • cardiac insufficiency • urinary 5-HIAA (5-hydroxyindole acetic acid) is high (5- HIAA is a metabolite of serotonin; serotonin is derived from tryptophan)
  97. 97. Cautions concerning the use of nicotinic acid in large doses • as an acid, it can erode gastrointestinal mucosa leading to ulceration • it also causes a depletion of glycogen stores and fat reserves in skeletal and cardiac muscle • additionally, there is an elevation in blood glucose and uric acid production • for these reasons, nicotinic therapy is not recommended for diabetics or persons who suffer from gout
  98. 98. Ascorbic acid • vitamin C; anti-scorbutic vitamin (scurvy) • structure is reminiscent of glucose • produced in plants from glucose via the uronic pathway • the enzyme gulonolactone oxidase converts gulonolactone to ascorbic acid • exists in the enolic and ketonic forms • sources: citrus fruits, tomatoes, green peppers, strawberries, cantaloupe, cabbage, turnips, peas, lettuce and aspargus
  99. 99. ASCORBIC ACID AND DEHYDROASCOBIC ACID HO HO O O CH OH CH2OH O O O O CH OH CH2OH
  100. 100. Ascorbic acid • Biochemical functions: – Production and maintenance of collagen • Proline --------hydroxyproline • Lysine -------- hydroxylysine – Mitochondrial electron-transport chain (cytochrome C) – Metabolism of tyrosine • Tyrosine ----- p-hydroxyphenylpyruvic acid---- 2,5- dihydroxyphenylacetic acid (homogentisic acid)
  101. 101. Proline hydoxylase: (collagen formation) Dopamine-beta hydroxylase ( neurotransmitter formation) N O N O HO vitamin C; O2 proline hydroxylase NH2HO HO NH2HO HO OH dopamine norepinephrine dopamine beta hydroxylase O2; Vitamin C
  102. 102. O OHO OH OHHO O OHO OH OO O Anti-oxidant properties of vitamin C: helps prevent damage to cellular proteins and DNA Normal metabolic processes in the cell lead to the generation of reactive oxidizing agents such as superoxide Superoxide can react with and damage protein and DNA, leading to cellular changes that can lead to premature aging and cancer Vitamin C reacts with superoxide, thus preventing this damage
  103. 103. Ascorbic acid – conversion of folic acid to THFA – hydroxylation reactions of cholesterol to cholic acid – hydroxylation of tryptophan to 5- hydroxytryptophan – regulation of cholesterol biosynthesis in the adrenal gland – aids in the absorption and utilization of iron – antioxidant properties may inhibit formation of nitrosamines during digestion of protein
  104. 104. Ascorbic acid • defiency: scurvy – hemorrhage from mucous membranes, mouth and GIT, skin and muscles – gingivitis: swelling, tenderness, redness and ulceration of gums – loosening or loss of teeth – swelling of joints – rarefaction of bones and dentine
  105. 105. Ascorbic acid • requirements: • children: 30 mg • adults: 40 –80 mg • pregnancy: 100 mg • therapeutic uses • scurvy • idiopathic methemoglobinemia • questionable use: common cold
  106. 106. Vitamin B12
  107. 107. Vitamin B12 • cyanocobalamin (Redisol) • hydroxocobalamin (Alpha redisol) • function • deficiency • hematological sequelae • neurological sequelae
  108. 108. Vitamin B12 • synthesized by bacteria only • red in color, levorotatory and stable to heat • commercially available either as cyano or hydroxocobalamin • stored in the liver as the coenzyme • absorbed only in the presence of the intrinsic factor (a glycoprotein released by parietal cells) • transported to tissues via transcobalamin II • present in foods such as liver, fish, eggs, milk • absent in vegetables and fruits
  109. 109. Vitamin B12 • by far the most complex vitamin in structure • made up of a planar corrin ring (4 pyrroles) • the only vitamin that possesses a metal ion (cobalt) as part of its structure • the major cofactor form of B12 is adenosylcobalamin or 5’- deoxyadenosylcobalamin • small amounts of methylcobalamin also occur (intermediate in methyl transfer reactions)
  110. 110. Vitamin B12 • the corrin ring is similar to the porphyrin ring system found in hemoglobin except that in corrin 2 of the pyrroles are linked directly (without methylene bridges) • the cobalt is coordinated to the 4 pyrrole nitrogens • one of the axial cobalt ligands is a nitrogen of the dimethylbenzimidazole group • the other axial ligand may be CN, OH, CH3 or the 5’-carbon of a 5’-deoxyadenosyl group
  111. 111. N N NN CH 3 CH 3 H2NCOCH 2CH 2 H3C H2NCOCH 2 CH 2CONH 2 H2NCOCH 2 CH 3 H2C CH 2CH 2CONH 2 CH 3 CH 3 CH 2 NH O CH 2CONH 2 O H3C P O O O OH HO N N CH 3 CH 3 Co CN CH 3 H3C H VITAMIN B 12 corin nucleus benzylimidazole cobalt coordinated
  112. 112. Vitamin B12 • biochemical functions (mediated by coenzymes) • mutase reaction (rearrangement reaction – methylmalonyl CoA to succinyl CoA (lipid metabolism) • methylation reactions – uracil to thymine – homocysteine to methionine – aminoethanol to choline • activation of amino acids for protein synthesis • ribonucleotides to deoxyribonucleotides for DNA synthesis in certain bacteria
  113. 113. Causes of B12 deficiency • Pernicious anemia (autoimmune gastritis against parietal cells - loss of intrinsic factor) • rarely due dietary deficiency • N2O/oral contaceptive drugs • intestinal parasite • gastrectomy • chronic gastritis • Schilling test
  114. 114. Diagnosis of B12 deficiency • Schilling test • distinguishes deficiency caused by pernicious anemia with that caused by malabsorption • compares absorption in radiolabeled B12 with intrinsic factor and radiolabeled B12 without intrinsic factor • in pernicious anemia the B12 with intrinsic factor will be absorbed while the B12 by itself will not • in malabsorption neither will be absorbed
  115. 115. Manifestation of B12 deficiency • macrocytic megaloblastic anemia • megaloblasts are abnormal erythroid precursors in bone marrow (most cells die in the bone marrow) • reticulocyte index is low • hyperchromic macrocytes appear in blood • anemia reflects impaired DNA synthesis • other cells may be involved (leukopenia, thrombocytopenia • spinal cord degeneration (irreversible) • swelling, demyelination, cell death • neurological disease • results from deficient methylmalonyl-CoA mutase • this cannot be treated with folic acid!!
  116. 116. Treatment of B12 deficiency • use IM cyanocobalamin or hydroxocobalamin • administer daily for 2 - 3 weeks, then every 2 - 4 weeks for life • monitor reticulocytosis early to assure treatment is working (reticulocyte count should go up) • monitor potassium levels to ensure hypokalemia does not occur due to excessive RBC synthesis
  117. 117. Folic acid • MOA • deficiency • use • drug interactions with folic acid
  118. 118. N N N N N H C N CH H OH H2N O COOH COOH FOLIC ACID Chemically composed of pteroic acid (pteridine and PABA) and glutamic acid Also known as folacin, vitamin M and pteroylglutamic acid Widely distributed in leaves (foliage) of plants
  119. 119. FOLIC ACID • absorbed by both active and passive transport • on the average we absorb 50 -200ug per day (about 10 -25% of dietary intake) • storage is in the form of 5-methyl THF (5 -20 mg) • found in green vegetable, dietary yeasts, liver, kidney • bacteria synthesize their own folic acid (dihydropteroate synthetase)
  120. 120. Folic acid • Biochemical functions – one carbon fragment transfer (formyl, methyl, hydroxymethyl) • conversion of homocysteine to methionine • conversion of serine to glycine • synthesis of thymidylic acid • synthesis of purines (de novo) • histdine metabolism • synthesis of glycine
  121. 121. PURINE CARBONS DERIVED via FOLATE N N N N NH2 DNA N N N N O DNA H2N H ADENINE (A) GUANINE (G)
  122. 122. BIOCHEMICAL ACTIVATION OF FOLIC ACID FOLIC ACID 7,8-DIHYDROFOLIC ACID (DHFA) TETRAHYDROFOLIC ACID (THFA)N5, N10-METHYLENE TETRAHYDROFOLIC ACID N5-FORMYL TETRAHYDROFOLIC ACID (LEUCOVORIN, FOLINIC ACID, CITROVORUM FACTOR) OTHER FORMS OF THFA: N 5-METHYL THFA N 5-FORMIMIDO THFA N10-FORMYL THFA N5, N10-METHENYL THFA
  123. 123. Deficiency of folic acid • Inadequate intake • defective absorption (most common) • sprue • gastric resection and intestinal disorders • acute and chronic alcoholism • drugs (anticonvulsants and oral contraceptives) • pregnancy • pellagra
  124. 124. Deficiency of folic acid • abnormal metabolism of folates • folic acid antagonists (dihydrofolate reductase inhibibitors - methotrexate, pyrimethamine, trimethoprim) • enzyme deficiency • vitamin B12 deficiency • oral contraceptives • increased requirement • pregnancy, infancy
  125. 125. METHOTREXATE N N N N NH2 H2N CH2 N CH3 N CH H O (CH2)2-COOH COOH METHOTREXATE Inhibits enzyme dihydrofolate reductase (DHFR) which is necessary for maintaining pool of reduced folates required for DNA synthesis
  126. 126. METHOTREXATE – also known as amethopterin or MTX – a potent inhibitor of dihydrofolate reductase which catalyzes the conversion of folic acid to tetrahydrofolic acid (THFA) – THFA acts as an acceptor of a one-carbon unit from either formate or formaldehyde – 5-formyl THFA is also known as folinic acid or the citrovorum factor (leucovorin) – THFA one-carbon carriers are important in the synthesis of purines, thymine, choline, and other important cellular constituents – MTX is used in treating acute lymphocytic leukemia in children, choriocarcinoma, osteogenic sarcoma, carcinomas of the head, neck, bladder and testis – in lower doses: treatment of psoriasis and rheumatoid arthritis
  127. 127. – diaminopyrimidines inhibitors of dihydrofolate reductase – have activity in both bacterial and protozoal organisms – more effective if used in combination with another drug – pyrimethamine is more selective for protozoal enzyme than trimethoprim – used in treatment of malaria and PCP N N NH 2 CH 2CH 3 H2N Cl PYRIMETHAMINE N N CH 2 OCH 3 OCH 3 OCH 3 H2N NH 2 TRIMETHOPRIM (DARAPRIM)
  128. 128. The fat soluble vitamins By Henry Wormser Professor of Medicinal Chemistry
  129. 129. Fat soluble vitamins • Vitamins A, D, K and E are the fat- soluble vitamins • excessive use of vitamins A and K can lead to toxicities • fat soluble vitamin tend to be stored in fatty tissues of the body and in the liver
  130. 130. Vitamin A • Exits in 3 forms: • all trans-retinol • long chain fatty acyl ester of retinol (main storage form) • retinal (the active form in the retina) • retinoic acid is also considered to be physiologically active • provitamin A or carotene can be converted to retinol in vivo
  131. 131. Vitamin A • recommended intakes are expressed in retinol equivalents (RE) 1 RE = 1 mcg of retinol = 6 mcg of β-carorene = 12 mcg other carotenes • older usage expressed activity in USP units or International units (IU). These were based on biological activity in the vitamin a-deficient rat (1 IU = 0.3 mcg of retinol)
  132. 132. CH3 CH3H3C CH3 CH2OH CH3 VITAMIN A (RETINOL) Vitamin A contains 5 conjugated double bonds which are key to some biological actions Isolated in impure form by McCollum in 1915 RDA: 0.7 mg
  133. 133. Vitamin A • Diseases of deficiency: – Nigh blindness and xerophthalmia (dry eye) – Skin disorders – Lack of growth • Hypervitaminosis: – A serious potential problem (CNS disorders; birth defects)
  134. 134. CH3 CH3 H3C CH3 H3C CH3 H3C CH3CH3 CH3 β-carotene CH3 CH3 H3C CH3 CH3 OH CH3 CH3 H3C CH3 CH3 O H liver O2 retinal (active form in vision) CH3 CH3 H3C CH3 CH3 O COOH CH3 CH3 H3C CH3 CH3 retinoic acid ("hormonally-active form")R O vitamin A acetate (R = CH3) vitamin A palmitate (R = C16H33 retinol (from diet)
  135. 135. Vision and the role of vitamin A • photoreception is the function of 2 specialized cell types: rods and cones • both types of cells contain a photosensitive compound called opsin – in rod cells opsin is called scotopsin and the receptor is called rhodopsin or visual purple – rhodopsin is a serpentine receptor imbedded in the membrane of the rod cell; it is a complex between scotopsin and 11-cis retinal
  136. 136. Vision and the role of vitamin A • intracellularly, rhodopsin is coupled to a G- protein called transducin • when rhodopsin is exposed to light, it is bleached releasing the 11-cis-retinal from opsin • absorption of photons by 11-cis-retinal triggers the conversion to all-trans-retinal (one important conformational intermediate is metarhodopsin II); also there is a change in conformation of the photoreceptor
  137. 137. Vision and the role of vitamin A • these transformations activate a phosphodiesterase (which hydrolyzes c-GMP to GMP) • c-GMP is necessary to maintain the Na+ channels in the rods in the open conformation • with a decrease in c-GMP, there occurs a closure of the Na+ channels, which leads to hyperpolarization of the rod cells with concomittant propagation of nerve impulses to the brain
  138. 138. H3C CH3 CH3 CH3 H3C N H N N O H H 11-cis Schiff's base lysine chain of opsin CH3H3C H3C CH3 N CH3 N NO H H H 1. light 2. isomerization of retinal 3. change in shape of rhodopsin 11-trans retinal signal transduction nerve impulse RHODOPSIN (11-cis retinal + opsin)
  139. 139. Additional role of retinol • retinol also functions in the synthesis of certain glycoproteins and mucopolysaccharides necessary for mucous production and normal growth regulation • this is accomplished by phosphorylation of retinol to retinyl phosphate which then functions similarly to dolichol phosphate
  140. 140. CH3 CH3H3C CH3 COOH CH3 RETINOIC ACID (RETIN A) Retinoic acid (Retin-A) is important for cellular differentiation; It controls cellular growth – particularly cell growth Used in the treatment of acne; also used as an anti-wrinkle agent (Retin A, Retin A micro, Avita, Renova) Also used orally to treat acute promyelocytic leukemia (APL) Product used is Vesanoid (10 mg capsules)
  141. 141. CH3 CH3H3C CH3 CH3 COOH ISOTRETINOIN (ACCUTANE) Isotretinoin or accutane is a modification of retinoic acid; it contains a 13-cis double bond and is orally effective Used in the treatment of severe acne
  142. 142. CH3O CH3 H3C CH3 CH3 CH3 COOH ACITRETIN (SORIATANE) An aromatic analog of retinoic acid; orally effective and used in the management and treatment of psoriasis
  143. 143. Etretinate (Tegison) CH3 H3C CH3O CH3 CH3 CH3 O OC2H5 Esterified form of acitretin; also used orally in the treatment of recalcitrant psoriasis; 10 and 25 mg capsules
  144. 144. Alitretinoin (Panretin) CH3H3C CH3 CH3 CO2H CH3 9-cis-retinoic acid (Alitretinoin) Currently used as a 0.1% gel for the topical treatment of cutaneous lesions in patients with AIDS-related Kaposi sarcoma
  145. 145. BEXAROTENE (Targretin) CH3 H3C CH3 H3C CH3 COOH CH2
  146. 146. Bexarotene (Targretin) • indicated for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma • usually the patients receiving this drug have failed to respond to other treatment protocols • pregnancy (Category X drug)
  147. 147. Adapalene (Differin) OCH3 HO2C Adapalene Used as a 0.1% gel in the treatment of acne vulgaris
  148. 148. Tazarotene (Tazorac) N C C S H3C CH3 EtO2C Topical treatment of patient with facial acne vulgaris of mild to moderate severity; gel 0.05%, 0.1%
  149. 149. Vitamin A toxicity • vitamin A is higly toxic when taken in large amounts either acutely or chronically • may occur with 200 mg (666,000 IU) in adults or half this amount in children • signs include headache, nausea and vomiting, increased cerebrospinal fluid pressure, blurred vision and bulging of the fontanelle in infants
  150. 150. Chemical name Abbreviation Generic name Vitamin D2 D2 ergocalciferol Vitamin D3 D3 Cholecalciferol 25- hydroxyvitamin D3 25(OH)D3 calciferol 1,25-dihydroxy vitamin D3 1,25-(OH)3 Calcitriol 24,25-dihydroxy vitamin D3 24,25(OH)2D3 Secalcifediol
  151. 151. Vitamin D • There are 2 major precursor forms: • 7-dehydrocholesterol • ergosterol • UV irradiation affords cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) • Discovery: • 1890 – sunlight prevents rickets • 1924 – Steanbock and Hess found that irradiating certain foods produced vitamin D2 • 1970 – hormonally active form of vitamin D discovered
  152. 152. Vitamin D • RDA – 20 μg (required in minute amounts) • disease of deficiency: rickets • Malformation of bones – due to improper bone mineralization • Hypervitaminosis • Toxic dose only 10X higher than the RDA • Causes hypercalcemia – can lead to cardiac arrest • vitamin D is not a vitamin (or a cofactor) – it is a steroid hormone
  153. 153. HO OH CH 3 CH 2 HO 7-DEHYDROCHOLESTEROL PRE-D 3 D3 (CHOLECALCIFEROL)
  154. 154. Biological functions • Calcium homeostasis – it is critical for the body to maintain the proper calcium level in the blood stream – Intestinal calcium absorption: acts as a signal to tell intestinal cells to take up more calcium from the gut – Bone calcium mobilization • Signals osteoclast (bone cells) to release calcium into the blood stream in response to low calcium levels
  155. 155. Biological functions • Cellular differentiation – much less well understood – signal to bone marrow cells to change into other cells leukemia cell 1α,25(OH)2 vitamin D3 normal white blood cell derived from bone marrow grows at the proper rate high levels Problem: 1α,25(OH)2-D3 causes hypercalcemia
  156. 156. Various analogs of vitamin D OH HO synthetic analog of vitamin D Potential use: -anti-cancer agent -immunosuppressive
  157. 157. CH2 HO OH CH3 H3C CH3 DOXERCALCIFEROL (HECTOROL)
  158. 158. Doxercalciferol (Hectorol) • a synthetic vitamin D analog that undergoes in vivo metabolic activation to 1-α,25- dihydroxyvitamin D2 • Activation does not require involvement of the kidneys • Used in hyperparathyroidism in patients undergoing chronic renal dialysis • Initial dose 10 mcg orally 3 times per week
  159. 159. HO H OH CH3 H OH PARACALCITOL (ZEMPLAR)
  160. 160. PARICALCITOL (Zemplar) HO H OH CH3 H OH PARACALCITOL (ZEMPLAR) A synthetic vitamin D analog indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure
  161. 161. CH2 HO OH CH3 H H3C OH CALCIPOTRIENE (DOVONEX)
  162. 162. Calcipotriol (Dovonex) H3C CH2 HO OH OH a vitamin D derivative approved for the treatment of psoriasis. Mechanism of action is unknown. Receptor affinity is similar to that of calcitriol, but is less than 1% as active in regulating calcium metabolism
  163. 163. Calcipotriene • An analog of vitamin D3 with a modified side-chain containing a 24-OH group and a cyclopropyl group • binds strongly to the D3 receptor on keratinocytes in skin and it suppresses their proliferation (used in psoriasis) • has only about 0.5% of the activity of D3 on calcium and phosphorus metabolism
  164. 164. Dihydrotachysterol (DHT) H3C HO CH3 A reduction product of vitamin D-2 Used in the management of hypoparathyroidism has only 1/450th the antirachidic activity of vitamin D-2
  165. 165. Vitamin K • the koagulation vitamin • exists in 2 forms: – plant origin: phylloquinone or vit K1 – bacterial origin: menaquinones or vit K2 • also certain synthetic quinones have vitamin K activity – menadione (vitamin K3) – menadiol sodium phosphate (vitamin K4)
  166. 166. O O CH3 CH3 CH3 CH3 3 PHYTONADIONE (VITAMIN K 1; PHYLLOQUINONE)
  167. 167. O O CH3 CH3 CH3 CH3 n = 1 -12 MENAQUINONE (VITAMIN K 2 SERIES)
  168. 168. O O CH3 MENADIONE (VITAMIN K3)
  169. 169. CH2 CO2 CH2 CH2 CH CO2O2C CO2 O2 OH CH3 R OH CH3 R O O O NADH NAD WARFARIN & OTHER ANTICOAGULANTS ANTIVITAMIN K ACTION OF ORAL ANTICOAGULANTS
  170. 170. Vitamin E • alpha (E1), beta (E2) and gamma(E3) tocopherol • sources: plant oils (corn, peanut, wheat germ), green leafy vegetables, meat, eggs • value resides in the antioxidant properties of vitamin E (may prevent the formation of peroxides)
  171. 171. O CH3 H3C HO CH3 CH3 CH3 CH3 CH3 CH3 ALPHA TOCOPHEROL ALPHA TOCOPHEROL Found in a variey of different sources (primarily vegetable fats)
  172. 172. Vitamin E • Estimated requirements: 5 mg/day + 0.6 mg/day of unstaurated fat • Biological function – antioxidant for fatty acids – Acts like vitamin C; prevents lipid peroxidation and/or damage to cells by lipid hydroperoxides
  173. 173. Uses for vitamin E • hemolytic anemia in premature infants, unresponsive to B12, Fe and folic acid • macrocytic megaloblastic anemia seen in children with severe protein-calorie malnutrition
  174. 174. Other coenzymes O O CH3 CH2CH3O CH3O CH C CH3 CH2 H 10 Coenzyme Q (Ubiquinone) N N N NH2N H H OH CHH CH OH CH3 OH Tetrahydrobiopterin Serves as entry into the electron- transport chain Involved in the conversion of phenylalanine to tyrosine
  175. 175. 09/12/02

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