V6 vitaminb6

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  • Generally are light sensitive and this depend on pH
    PN, PL, PM heat stable in acid, labile in alkali
    PLP covalently bound to enzyme (lysine)
  • Free and phosphorated forms
  • Glycosylated: conjugated (5-glucoside-pyridoxine) release pyridoxine only when food treated with alkali or B-glucosidase
    Milk: heat sterilization converts PL to PM (storage, formation of other products, less available)
  • Prior intake has no effect
    50% of B6 in orange juice as pyridoxine-5-0-glucoside
    Availability of glycosylated form is about 58%
  • Absorption of phosphorelated forms can occur, but to a very limited extent
    PL and PLP are bound to albumin to protect from hydrolysis
  • PL concentration in RBC is about 4 times that in plasma
    In liver: PLP bound to glycogen phosphorylase is about 10%
  • Increase in circulating PLP following exercise
  • The 3 non-phosphorylated forms are phosphorylated by kinase enzyme (ATP, Zn)
    Dephosphorylated PLP  PL  4-pyridoxic acid by NAD dependent dehydrogenase or FAD dependent aldehyde oxidase (pyridoxal oxidase), in human only pyridoxal oxidase
    Conversion of PL to 4-PA is irreversible
  • PLP binding with protein (metabolic trapping)
    In fasting plasma PL and PLP: 70-90% of B6, next PN, PMP and Pm, but no PNP
  • GABA: gama aminobyutyric acids
  • Gene expression: high IC PLP  Low transcriptional response to hormones
    Induction of cytosolic aspartate aminotransferase (AAase) by hydrocortisone is suppressed by administration of PN due to
    Low expression of AAase gene by inactivation of binding activity of glucorticoid receptors to glucorticoid responsive element in AAase gene
    Gene expression, not only hormone responsive and PLP-dependent enzymes..
    Albumin: enhance gene expression by increased amino acids and low PLP
    Blood pressure, neurotransmitter and other mechanisms
  • B6 deficient rats:
    low body fat
    Low liver lipid (TG, not cholesterol)
    High protein (fatty liver, degradation)
    Synthesis: not clear
    Conversion of linoleic to arachidonic
    Accumulation of linoleic and a-linolenicacid
    Low linoleic desaturation and a-lenolenic elongation
    Relation between phosphotidylcholine and D desaturase, altered PC may affect linolenic acid desaturation
    Low methylation of phosphoethanolamine  low PC
    SAM high (s-adenosyl-methionine) no methylation
    Arachidonic acid and choresterol
    Monkey: B6 deficient diet: high cholesterol
    Human: no clear relation
    Positive correlation between PLP and HDL
    PLP for carnitine synthesis
    Clarification is needed
  • Rats on low B6 diet for 4 weeks given 2g of L-tryptophan, low urinary excretion of n-ch3-nicotinamide and n-CH3-2-pyridone-5-carboxamide
  • V6 vitaminb6

    1. 1. Vitamin B6 Omar A Obeid NFSC 315
    2. 2. Vitamin B6 • Gyorgy 1934: Antidermatitis (Acrodynia) factor in rats. • Crystallized (1938) by 3 groups • Synthesized (1939) in USA and Germany • 1945: Three forms of the vitamin
    3. 3. VITAMIN B6 O NH2 HO HO OH PYRIDOXAL PYRIDOXAMINE OH OH N OH N N HO H PYRIDOXINE
    4. 4. Vitamin B6 • Exists as several vitamers – Interchangeable – Pyridoxine (PN): alcohol (OH) form – Pyridoxal (PL): aldehyde form – Pyridoxamine (PM): amine (NH2) form • Each has a 5’-phosphate derivative – PNP, PLP, PMP – Function as coenzymes
    5. 5. Vitamin B6 Structures O CH2OH O P - O CH2OH OH H2C O+ N H CH3 Pyridoxine phosphate (PNP) O P - NH2 H C O O CH3 + N H Pyridoxamine (PM) CH3 + N H Pyridoxal (PL) + N H Pyridoxine (PN) O OH HOH2C OH HOH2C CH3 O CH2 C OH HOH2C NH2 H OH H2C O+ N H CH2 O CH3 Pyridoxal phosphate (PLP) O P O - O- OH H2C + N H CH3 Pyridoxamine Phosphate (PMP)
    6. 6. Chemistry • • • • • Colorless crystalline solid Soluble in water and alcohol Stable to heat (-al and -amine less) Decompose in alkali and light Pyridoxal 5-phosphate and pyridoxamine 5-phosphate are the coenzyme forms.
    7. 7. Sources • All vitamers are found in food • Pyridoxine – Most stable – Found mainly in plants – Bananas, navy beans, walnuts • Pyridoxamine and Pyridoxal – Found in animal products – Sirloin stead, salmon, and light meat of chicken.
    8. 8. Vitamin B6 Content of Foods Food Dairy products Milk Yogurt Cheeses Meat Beef Chicken Lamb Pork Ham Calf liver Herring Haddock Tuna Oysters Shrimp Vitamin B6(mg/100g) 0.04 0.05 0.04-0.08 0.33 0.33-0.68 0.28 0.35 0.32 0.84 0.37 0.18 0.43 0.05 0.10 Glycosylated(%) _ _ _ _ _ _ _ _ _ _ _ _ _ _
    9. 9. Vitamin B6 Content of Foods Food Vitamin B6(mg/100g) Cereals Corn meal Rice Polished Unpolished Wheat, whole Other Eggs Human colostrum Human milk Glycosylated(%) 0.20 _ 0.17 0.55 0.29 20 23 28 0.19 0.001-0.002 0.010-0.025 _ _ _
    10. 10. Vitamin B6 Content of Foods Food Vitamin B6(mg/100g) Glycosylated(%) Vegetables Asparagus Beans Broccoli Brussels sprouts Cabbage Carrots Cauliflower Celery Corn Onions Peas Potatoes Spinach 0.15 0.08-0.18 0.17 0.18 0.16 0.15 0.21 0.06 0.20 0.13 0.16 0.25 0.28 _ _ 66 _ 46 51-86 66 _ _ _ 15 32 50
    11. 11. Vitamin B6 Content of Foods Food Fruits Apples Grapefruit Oranges Peaches Strawberries Tomatoes NUTS Peanuts Pecans Walnuts Vitamin B6(mg/100g) Glycosylated(%) 0.03 0.03 0.06 0.02 0.06 0.10 _ _ _ _ _ 46 0.40 0.18 0.73 _ _ 7 Sources: USDA data; Leklem, J.E. (1996). In: “Present Understanding in Nutrition” (E.E. Ziegler and L.J. Filter,Jr.,eds.), 7th Ed., p.175. ISLI Press, Washington, D.C.
    12. 12. Concentrations (µg per 100g)and proportions of vitamin B6 derivatives in selected foods. Total B6 VEGETABLES Carrots FRUITS Apple raw Apple juice Orange Orange juice %P 206 18 104 87 83 55 33 26 39 42 %Free 29 %PNG 54 52 65 33 36 15 9 28 23 CEREALS Whole wheat bread White bread 79 16 39 42 33 51 51 8 NUTS/SEEDS Almonds Sunflower seeds Soyabean 137 605 267 5 14 34 95 34 49 0 52 18 Sources: Reynolds,1998; Bitsh and Schramm, 1992. %P=%Phosphorylated vitamers; %Free=%non-phosphorylated vitamers; %PNG=
    13. 13. Sources • Loss during refining of cereals (flour) • Large % Vitamin B6 can bound to proteins via amino or sulfhydryl groups. – Less available: resistant to hydrolysis and low B6 activity. • Vitamin B6 react with glucose and become glycosylated. – Less available • Storage: loss 10-50%
    14. 14. Vitamin B6 • Digestion – Phosphorylated vitamers must be dephosphorylated prior to absorption • Intestinal phosphatases • Absorption – PN, PL and PM absorbed primarily by non-saturable process (passive diffusion) • Absorption of dietary B6 ranges from 71-82% • Diffusion linked to phosphorylation: Jejunum and ileum. • Dephosphorylation by membrane bound alkaline phosphatase
    15. 15. Absorption of the B6 Vitamins Pyridoxamine Pyridoxal Pyridoxine PM PL PN PMP PLP PNP ADP ATP Mucosal Cell B6 Pi
    16. 16. Vitamin B6 • Within Enterocyte – PN phosphorylated to PNP • Pyridoxine kinase (ATP, Zn) – PL phosphorylated to PLP • Kinase (ATP, Zn) – PNP may be converted to PLP • Pyridoxine phosphate oxidase (FMN) • Blood – PLP is main form (~60%) of vitamin in blood • PL also exists • Both PL and PLP are bound to albumin – 0.1% of total B6 in plasma as PLP, bound to protein
    17. 17. Vitamin B6 • Erythrocytes – PL and PN (rapid simple diffusion)  PLP – Tight binding to Hb (role in transport!) • Liver – Stores about 5 to 10% or vitamin – Phosphorylation occurs within cytoplasm – PNP and PMP are converted to PLP – PL and PLP are released into blood for transport to extrahepatic tissues
    18. 18. Vitamin B6 • Requires removal of P by phosphatase to enter cells • Muscles (possess majority of PLP) – PLP must first be hydrolyzed to PL before uptake – Within cell rephosphorylated – 80-90% in muscle bound to glycogen phosphorylase – Decrease with low energy intake • B6 in body mainly as PLP • Human body store is 40-150mg, sufficient for 20-75 days
    19. 19. Metabolism • Interconversion of vatimers • Metabolism mainly in liver – PMP and PNP are converted to PLP by: • Pyridoxal phosphate oxidase require FMN – Dephosphrylation of PLP to PL to 4-PA • Intracellular level of PLP – Controlled by enzymatic hydrolysis • Excess PLP will be hydrolyzed to PL – Controlled by product inhibition of PNP/PMP oxidase
    20. 20. Metabolism/Excretion • Excess PL is converted to Pyridoxic acid (PA) – PA excreted in urine – PA excretion reflects recent vitamin intake • Newly formed PLP is not freely exchangeable with endogenous PLP • Major product for excretion is 4-pyridoxic acid • Urinary 4-pyridoxic acid is inversely related to protein intake • Interacts with folate and B12
    21. 21. Metabolic functions • • • • • • • Amino acid metabolism Gluconeogenesis/glycogen catabolism Niacin formation Nervous system Immune function Hormone modulation Lipid metabolism
    22. 22. Functions • Amino Acid Metabolism – PLP via formation of a Schiff base labilizes all the bonds around the alpha carbon of the amino acid – Schiff base • Product formed by an amino group and an aldehyde – The specific bond that is broken is determined by the enzyme • Decarboxylase, Transaminases, Aldolases
    23. 23. Transaminations • PLP and PMP serves as coenzymes – Aspartic amino transferase (AST) • Aspartate donates its amino group to an alpha keto acid forming OAA and a different amino acid – Alanine aminotransferase (ALT) • Alanine donates its amine group to an alpha keto acid forming pyruvate and a different amino acid
    24. 24. Transaminations • Phase I – The corresponding alpha keto acid (pyruvate) of the amino acid (alanine) is produced along with PMP • Phase II – New alpha keto acid (alpha keto glutarate) receives amino group from PMP producing the new amino acid (glutamate) and PLP
    25. 25. Decarboxylations • GABA Synthesis – Glutamate decarboxylase – Conversion of Glutamate to GABA • Serotonin Production – 5-Hydroxytryptophan decarboxylase – Conversion of 5-hydroxytryptophan to serotonin (5-hydroxytryptamine)
    26. 26. Metabolic interconversions of the B6 vitamers 4-PA PM PL PLP Transaminase PNPoxidase (FMN) Pase PLkinase Pase PLkinase Pase PLkinase PNP PNPoxidase (FMN) Aldehyde oxidase (FAD) Aldehyde dehydrogenase (NAD) PN PMP
    27. 27. Transulfhydrations and Desulfhydrations • PLP required for cysteine synthesis from methionine – Both cystathionine beta synthase (CBS) and cystathionase require PLP • PLP required for desulfhydration followed by transamination to generate pyruvate.
    28. 28. Other reactions • Cleavage – PLP required for removal of the methyl group from serine and transfer to THF • Glycine produced as well • Racemization – PLP required by racemases that catalyze interconversion of D- and L- amino acids • Synthesis – PLP necessary for synthesis of heme, niacin, histamine from histidine, carnitine, taurine, dopamine and more.
    29. 29. Effect of Protein Intake on Vitamin B6 Status Treatment Protein intake (g/Kg/d): 0.5 1.0 2.0 Vitamin B6 intake (mg/g protein): 0.04 0.02 0.01 Parameter (adequate value) Percentage of subjects with low values Urinary 4-pyridoxic acid(>3 mmol/day) 11 22 78 Urinary total vitamin B6(>0.5 mmol/day) 56 56 67 Plasma pyridoxal phosphate(>30 mmol/liter) 33 67 78
    30. 30. Gluconeogenesis/glycogen catabolism • Transamination and glycogen phosphorylase • Vitamin B6 deficient rats – Low liver and muscle glycogen phosphorylase – No effect on B6 conc in Muscle, unlike calorie restriction • Rats: IV. B6 (300mg/kg) – Low liver glycogen and high plasma glucose • In human: – No clear relation
    31. 31. Nervous system • Neurotransmitters: serotonin, taurine, dopamine, norepinephrine, histamine, GABA • Rats: mother deficient in B6: – Offspring: Brain abnormalities • Infant fed formula low in B6 – Abnormal electroencephalograms (EEGs) • Adults with B6 deficiency • Abnormal EEGs with high protein diet
    32. 32. B6 and synthesis of neutransmitters Glutamate Glutamate decarboxylase γ – aminobutyric acid (GABA) O2 Tryptophan CO2 5 hydroxy tryp Hydroxylase 5-OH-Tryptamine PLP (Serotonin)
    33. 33. CO2 O2 Tyrosine DOPA Dopamine O2 Hydroxylase Norepinephrine SAM CH3 Epinephrine
    34. 34. Immune system • serine transhydroymethylase (PLP) for 1C metabolism (nucleic acid synthesis)  immune function • Vitamin B6 deficient animals: – Low lymphocyte production, antibody response to antigens, cell mediated immunity • Human: – Elderly with impaired immune system: respond to 50mg PN/d – Young: Marginal deficiency : no effect – Health elderly: relation between B6 and immunity (IL2)
    35. 35. Effect of Vitamin B6 Status on Mitogenic Responses and Interleukin 2 Production by Peripheral Blood Mononucleocytes of Elderly Humans Parameter Baseline B6 deprived B6 supplemented Mitogenic response Concanavalin A Phytohemagglutinin Staphylococcus aureas 120 100 115 70 70 60 190 100 200 IL-2 production (Ku/Liter) 105 40 145 Source: Meydani, S.N., Ribaya-Meradi, J.D., Russel, R.M., Sahyoung, N., Morrow, F.D., and Gershoff, S.N. (1991). Am. J. Clin. Nutr. 53, 1275-1280 .
    36. 36. Erythrocyte function • Binding of PL to α-chain Hb increases O2 binding affinity • Binding of PLP to β-chain Hb decreases O2 binding affinity • PLP cofactor for δ-aminolevulinic acid synthetase (heme synthesis) • B6 deficiency: – Microcytic anemia – Pyridoxine responsive anemia
    37. 37. Hormone modulation/gene expression • Reversible reaction with receptors for: – Estrogen, androgen, progesterone, glucocorticoid at lysine residues. • Vitamin B6 deficient rats: – – – – – H-estradiol: more incorporation at uterine tissues Zn and B6 deficiency: more interaction No of estrogen receptors not affected mRNA albumin increased (7 times) mRNA of cytosolic aminotransferase (7 times) 3 • Vitamin B6 may be a modulator of gene expression
    38. 38. Lipid metabolism • Similarity between EFA and B6 deficiencies • B6 deficient rats: low body fat • Conversion of linoleic to arachidonic • Arachidonic acid and cholesterol • PLP for carnitine synthesis – Clarification is needed
    39. 39. Cellular processes affected by PLP Cellular process Function 1-C metabolism, hormone modulation Immune function Glycogen phosphorylase, transamination Gluconeogenesis Tryptophan metabolism Niacin formation Heme synthesis, transamination, O2 affinity Red cell metabolism and formation Neurotransmitter synthesis, lipid metabolism Nervous system Hormone modulation, binding of PLP to lysine on hormone receptors Hormone modulation
    40. 40. Nutrient Interactions • Vitamin B6 is interrelated with Riboflavin – Riboflavin is coenzyme of PNP/PMP oxidase which converts PNP/PMP to PLP • Vitamin B6 is interrelated with Niacin – Niacin is coenzyme for aldehyde dehydrogenase which oxidizes PL to PA. – Conversion of tryptophan to niacin
    41. 41. Drug-vitamin B6 interaction Drug Examples Mechanism of interactions Hydrazines Iproniazid, isoniazid, hydralazine Reacts with Pl and PLP to forms a hydrazone Antibiotic cycloserine Reacts with PLP to form an oxime L-DOPA L-3,4-(HO)2phenylalanine Reacts with PLP to form tetrahydroquinoline derivatives Chelator Penicillamine Reacts with PLP to form thiazolidine Oral contraceptives Alcohol Increase enzyme level in liver and other tissues, retention of PLP Ethanol Increased catabolism of PLP
    42. 42. Vitamin B6 and disease • Coronary heart disease – Altered S-AA metabolism – Hcy elevation – Cystathionine β-synthase deficiency: • Arteriosclerosis – PLP and atherosclerosis: independent of Hcy and cholesterol – Relation with cholesterol – Immunity
    43. 43. Vitamin B6 and disease • HIV/AIDS – – – – B6 and progression: inverse Low status PLP binds to CD4 receptors PLP in a noncompetitive inhibitor of HIV-1 reverse transscriptase • Premenstrual syndrome – – – – PLP status similar between PMS and non-symptoms B6 suppl: improvement in some symptoms 150-200mg!! Cell transport competition, receptor
    44. 44. Vitamin B6 and disease • Sickle cell anemia – Low level – 100mg PN-HCl (2m): low severity, frequency and duration of painful crisis – PL and PLP binding to Hb • Asthma – Low PLP status – 100mg: PN-HCl: low duration, occurrence and severity – Theophylline: Low plasma and RBC PLP • Carpal tunnel syndrome – Most studies: PN suppl relif symptoms of pain and numbness in hands
    45. 45. Vitamin B6: High doses • Is toxic in pharmacological amounts • Chronic ingestion of 2-6 g pyridoxine/d may cause sensory neuropathy – Signs similar to deficiency • Has been used to treat a variety of conditions – Atherosclerosis, carpal tunnel syndrome, premenstrual syndrome, depression, muscular fatigue. • Rats (500-100mg/kg) – Decrease in testis epididymis, prostate gland, mature spermatid counts
    46. 46. Dietary Reference Intakes (DRI) For Vitamin B6 Females Males RDA (mg/d) RDA (mg/d)/ U L** (mg/d) 0- 6 months 0.1* 0.1* ND 7-12 months 0.3* 0.3* ND 1- 3 yrs. 0.5 0.5 30 4- 8 yrs. 0.6 0.6 40 9-13 yrs. 1.0 1.0 60 14-18 yrs. 1.2 1.3 80 19-50 yrs. 1.3 1.3 100 > 50 yrs. 1.5 1.7 100 1.9 - 80 1.9 - 100 2.0 - 80 2.0 - 100 Life stage group Infants Children Pregnancy < 18 yrs. > 18 yrs. Lactation < 18 yrs. > 18 yrs From Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington, DC: National Academy Press, 1998.
    47. 47. Vitamin B6 • 1989 RDA=1.6 - 2.0 mg/d – Based on protein intake • 1998 RDA – Adult = 1.3 mg/d • UL: – Adult: 100mg/d
    48. 48. Deficiency • Rare • Sign of deficiency can be quickly corrected by administration. • Deficiency Signs – Fatigue, cheilosis, glossitis, seizures, convulsions in infants, hypochromic, microcytic anemia (impaired heme synthesis)
    49. 49. Pyridoxine (Vitamin B6) Pyridoxine deficiency: The scaling seborrhea-like dermatosis in this patient was induced in volunteers by giving the pyridoxine antagonist desoxypyridoxine. Such lesions have not been proved to occur spontaneously although it is suspected that some instances are due to pyridoxine deficiency.
    50. 50. Pyridoxine (Vitamin B6) Pyridoxine deficiency: The glossitis in this patient was induced in volunteers by giving the pyridoxine antagonist desoxypyridoxine. This is undistinguishable from that due to deficiency of other B group vitamins.
    51. 51. Groups at Risk for Deficiency •Breastfed infants born with low Vitamin B6 •Elderly •Poor intake and possibly accelerated hydrolysis of PLP and oxidation of PL to PIC •Alcoholics •Conversion of PN and PM to PLP impaired •Persons on maintenance dialysis •Variety of Drug Therapies •Isoniazid, corticosteroids, anticonvulsants
    52. 52. Assessment • Direct: – Plasma PLP(>30nM) – Plasma total B6 (>40nM) – Urinary 4-pyridoxic acid (>3.0µmol/day) • Indirect: – Tryptophan loading (2g): xanturenic acid – Methionine loading (3g): Hcy, cystathionine – Erythrocyte transaminase stimulation • Dietary intake – Intake, B6:protein ratio (>0.02), PN-β-glucosidase • EEG pattern
    53. 53. Assessment of Status (Tryptophan Load) TRYPTOPHAN N-FORMYLKYNURENINE KYNURENINE Xanthurenic Acid 3-OH-KYNURENINE Kynureninase (PLP) 3-OH ANTHRANILIC ACID QUINOLINIC ACID NIACIN acetyl CoA acetoacetyl CoA
    54. 54. Assessment of Status • Erythrocyte Transaminase Index – Erythrocyte alanine aminotransferase – Erythrocyte aspartate aminotransferase – Look at the activity of the enzyme before and after addition of Vitamin B6 – A two-fold or more increase in activity of the enzyme after addition of vitamin B6 is indicative of deficiency – Less than a two-fold increase in activity is indicative of acceptable status

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