Water soluble vitamins

1. Water soluble vitamins Dr.S.Chakravarty, MD

2. A- ATP B- BIOTIN C- CO2 REM - VOMIT MAIN ATP SYNTHESIS DECREASEDATP Na+K+ PUMP FAILURE CELLS SWELL AND DIE KAPLAN Step 1 notes

3. v.ImpSOURCE OF e0 -1 for ETC Left untreated death !! U T DNA and RNA synthesis KAPLAN Step 1 notes

4. KAPLAN Step 1 notes SUBACUTRE COMBINED DEGENERATION 1)Regeneration of TETRAHYDROFOLATE (ACTIVE FOLATE )DNA and RNA synthesis ANYTHING THAT DAMAGES LIVER OR ANYTHING THAT INCTREASED AST/ALT ACTIVITY INCREASED NEED FOR PLP LESS HEMESMALL RBCs IRON NOT USED  IRON DEPOSITED IN PRECURSORS OF RBCSSIDEROBLASTS

5. ATP STOMACH ACIDITY AND VIT C Fe+3Fe +2 CoA KAPLAN Step 1 notes

6. Thiamine : B1 Source : unpolished rice and whole wheat.(Aleurone layer OF CEREALS ) PARBOILED RICE IS RICH IN THIAMINE Thiamin status is affected by: Food processing – washing, polishing etc. Anti-thiamine factors – Fresh water and shell fish (thiaminases), pyrithiamine. Ethanol ingestion / c/c alcoholism (MCC cause of DEFICIENCY ) Reduces thiamin intake Impairs intestinal absorption Alters phosphorylation of thiamin Increases excretion

7. Functions of B1: 1. Enzyme cofactor: (Thiamine pyrophosphate TPP or TDP) Oxidative decarboxylation reactions Pyruvate dehydrogenase α-ketoglutarate dehydrogenase α-keto acid dehydrogenase – branched chain amino acid metabolim. Transketolation reactions Transketolase – HMP pathway

8. 2. Thiamine Triphosphate (TTP) Nerve conduction Phosphorylation of membrane ion channels Regulates sodium conductance Neurotransmission Acetyl choline, Glutamate and GABA synthesis and utilization Increase neurotransmitter levels in brain.

9. Measurement of thiamine status: Erythrocyte transketolase activity: Lab investigation for B1 deficiency. xylulose-5-p + Ribose-5-p (ketose) (aldose) Glyceraldehyde-3-p + Sedo-heptulose-7-p (aldose) (ketose)

10. Deficiency of B1: Beriberi Wet beriberi Dry beriberi Infantile beriberi Wernicke-Korsakoff syndrome: Polyneuritis:

11. Wet BeriBeri: Cardiovascular manifestations edema palpitations breathlessness fatigue distended neck veins cause of death: high ouputcardiac failure Shoshin beriberi: cyanosis, shock, cardiomegaly

12. Biochemical basis of wet beriberi: Pyruvate Acetyl CoA (-) Lactate Acidosis Depression of vasomotor center Decreased Vascular resistance Peripheral vasodilatation

13. Vasodilation High cardiac output Reninangiotensinaldosterone system Cardiac failure Sodium and water retention Edema

14. Dry Beriberi (paralytic / nervous) CNS manifestations: muscle weakness gait disturbance paralysis calf muscle tenderness impairment of sensory, motor and reflex functions (distal segment of limbs > proximal segment)

15. Infantile beri-beri: Maternal malnutrition Age group: 2 – 3 months 3 forms Cardiac (acute fulminating) Aphonic Pseudomeningitic

16. Cerebral Beriberi: High risk groups: Alcoholism Chronic dialysis Clinical features: Wernicke’s encephalopathy – ataxia, confusion and opthalmoplegia. Korsakoff psychosis – amnesia and confabulation – impairment of conceptual function decreased spontaneity and initiative

17. Biochemical basis: Defective energy metabolism ATP synthesis Altered functions of neurons Degeneration of myelin sheaths Defective nerve conductance and neurotransmission Synthesis of neurotransmitters

18. Reason for decreased Neurotransmitters: Choline acetyl transferase PDH Pyruvate Acetyl Co-A Acetyl choline B1 Alpha ketoGlutarate Glutamate Glutamate decarboxylase B6 TCA cycle GABA

19. Riboflavin : B2 Heat stable, light sensitive , luminescent vitamin – UV light Vitamin B2 , lactoflavin, Warburg’s yellow enzyme Source – whole cereals, legumes (beans), eggs , milk

20. Co-enzyme forms: Flavokinase FAD synthase FMN – Flavin Mono Nucleotide FAD – Flavin Adenine Dinucletide Riboflavin FMN FAD

21. Functions: • Integral component of electron transport chain ATP SYNTHESIS • NADFMNCoQ • TCA cycle succinatedehydrogenase ATP SYNTHESIS • FATTY ACID OXIDATIONacylCoAdehydrogenase ATP SYNTHESIS • As a part of alpha ketoglutarate and isocitratedehydrogenase complex ( dihydrolipoatedehydrogenase)

22. Riboflavin deficiency:

23. Deficiency manifestations: Glossitis - inflammation of tongue Magenta red colour(glossitis ), Fissures, Atrophy of lingual papillae Cheilosis: fissures in lips Angular stomatits: inflammation at corners of mouth Conjunctivitis Oral-ocular-genital syndrome Angular stomatitis photophobia scrotal dermatitis

24. Niacin: B3 • Exists in two forms • Nicotinic acid (Niacin) • Nicotinamide (Niacinamide) • Two coenzyme forms of niacin • NAD+ • NADP+

25. Function: • Coenzymes are active participants in oxidation-reduction reactions – Dehydrogenases • Function in at least 200 reaction in cellular metabolic pathways • NAD+ • Participates in catabolic reactions • Electron and hydrogen ion acceptor • NADP+ • Anabolic reactions • Important in biochemical pathway for fatty-acid synthesis, steroid and bile acid synthesis.

26. Tryptophan can be converted to Niacin: Tryptophan FAD 3-OH-kynurenine kynureninase (-) B6 B6 3-OH-anthranallic acid Xanthurenic acid Niacin

27. Deficiency manifestation: • Pellagra • Dementia, Diarrhea, Dermatitis • If not treated can cause death • Develops about 50 to 60 days after a niacin deficient diet • Early symptoms • Loss of appetite, weight loss, and weakness • Mild symptoms • Indigestion, canker sores, vomiting, depression and fatigue

28. Pellagra like symptoms can be seen with: Niacin deficiency HartnupdiseaseLessabspn of Trp CarcinoidsyndromeexcessTrp going for Serotonin synthesis and less for Niacin synthesis Pyridoxine deficiencyKynureninase is not working INH (Isoniazid )administration ANTI-TUBERCULOUS DRUG  damages liver and increased AST/ALT activity + directly inhibits PLP formation

29. Uses of Nicotinic acid Atherosclerosis and Hyperlipidemias: By lowering VLDL levels and TG levels mainly .

30. Pyridoxine: B6 Three forms : Pyridoxine Pyridoxal Pyridoxamine – antioxidant Active form of B6 – Pyridoxal phosphate (PLP)

31. Functions of B6: Aminoacid metabolism: Transamination Deamination Decarboxylation Transulfuration Lipid metabolism : Sphingomyelin synthesis Carnitine synthesis Carbohydrate metabolism : Glycogenolysis – glycogen phosphorylase Gluconeogenesis –formation of alpha keto acids

32. Functions: Heme synthesis Catecholamine synthesis Niacin synthesis Modulation of hormone action – mainly steroids

33. Alaninetransaminase (ALT) Transamination reactions : Aspartatetransaminase (AST) Aspartate + α-ketoglutarate Oxaloacetate + Glutamate Alanine + α-ketoglutarate Pyruvate + Glutamate PLP PLP • Diagnostic enzymes in various liver diseases: • Helps in Gluconeogenesis – aminoacid to ketoacids

34. Decarboxylation reactions: Glutamate decarboxylase : Glutamate  GABA (inhibitory neurotransmittor) Histidinedecarboxylase : Histidine  Histamine DOPA decarboxylase: (catecholamine synthesis) DOPA  Dopamine

35. Transsulfuration : PLP PLP Cystathionineβsynthase: Homocysteine + serine Cystathionine Cystathionase: CystathionineHomoserine + Cysteine B6 deficiency Homocysteine Cardiovascular disease

36. Modulation of hormone action B6 - Remove hormone-receptor complex from DNA binding Terminate the action of steroid hormone B6 deficiency: Enhances steroid hormone sensitivity Increases risk for hormone dependent cancers of breast and uterus

37. Drugs inactivating PLP: Alcohol Isoniazid - Anti tubercular Carbidopa – used with DOPA in parkinsonism Penicillamine – chelating agent Oral contraceptive pills

38. Deficiency manifestation: Neurological manifestations: Peripheral neuritis convulsions Basis: Formation of catecholamine GABA levels Sphingolipid synthesis Demyelination Dermatitis - (pellagra like symptoms) Microcytichypochromic Anemia – decreased formation of Heme

39. Diagnosis of B6 deficiency: Decreased AST and ALT activity Methionine load test – Homocysteine and cystathionine in urine. Tryptophan load test – Xanthurenic acid

40. Pantothenic acid: B5 Contains Pantoic acid (derived from valine) and β-alanine (derived from aspartate) Carrier of acyl groups Involved in the metabolism of fat, proteins and carbohydrates Active form – Coenzyme A (Co-A) Acyl carrier protein.

41. Functions of Co-A: Cellular metabolism – Co-A derivatives Protein acetylation – Histones and Microtubules Protein acylation – palmitoylationmyristoylation of proteins – cell regulation. Detoxification of drugs – acetylation

42. Cellular metabolism of Co-A: Acetyl Co-A Malonyl Co-A HMG Co-A Fatty acyl Co-A Acetoacetyl Co-A Succinyl Co-A Palmitoyl Co-A TCA cycle fatty acid synthesis steroid metabolism Transport ketone body synthesis Heme synthesis sphinolipid synthesis

43. Deficiency manifestations; Fatigue, irritability low CoA levels energy production Neurological symptoms Numbness, muscle cramps acetyl choline formation Burning foot syndrome : Hypoglycemia : decreased acylation of receptors – increased binding of insulin.

44. Biotin: B7 Mitochondrial Co-enzyme for carboxylation reaction: Carboxylation require Bicarbonate, ATP and Biotin. 5 carboxylation reactions : Acetyl Co-A carboxylaseisoform –I –cytosol Acetyl Co-A carboxylaseisoform - II – outer mit Pyruvatecarboxylase Methyl crotonyl Co-A carboxylase Propionyl Co-A carboxylase

45. Biotin deficiency: causes Consumption of raw egg – Avidin ( binds biotin) Dialysis

46. Features of biotin deficiency Vitamin H – (Haar and Haut) Hair and skin in German Biotin deficient facies– unusual fat distribution with a characteristic rash. Symptoms : Periorificial dermatitis Conjunctivitis Alopecia Neurological – Tingling and numbness , depression , lethargy.

47. Biochemical basis: CNS features : Defect in Pyruvatecarboxylase lactic acidemia. Skin rash and hair loss – due to abnormal fatty acid metabolism mainly of omega -6 – fatty aicds. Biotinylation of histones – regulation of transcription and cell proliferation – is affected.

48. Folate metabolism: Intermediates Folic acid is present as various forms of Tetrahydrofolate : Acts as a co-enzyme by accepting, transfering, or modyfyingone carbon units that are attached to N5 or N10 position of folate. Active one carbon donors: Formyl THF – purine synthesis Methylene THF – pyrimidine synthesis Methenyl THF Formimino THF Predominant form in plasma – methyl THF (reduced) and inactive.

49. Folate metabolism:1. DNA synthesis2. Conversion of Homocysteine to methionine Purine synthesis DHFR DHFR Formyl THF Methenyl THF Methylene THF Folate Dihydrofolate THF Pyrimidine synthesis Methionine Methylenetetrahydrofolate reductase Homocysteine methyl transferase B 12 Homocysteine Methyl THF (reduced)

50. Pyrimidine synthesis: Methylene THF DHF d-UMP d-TMP Thymidylatesynthase Purine synthesis: Carbon 2 and 8 of the purine ring is donated by formyl THF