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Aminoacid metabolism -2

Aminoacid metabolism -2. Dr. S.Chakravarty MD . Metabolism of Sulphur containing Aminoacids :. Metabolic function of cysteine : Disulphide linkages in Proteins Formation of Glutathione (functional group is sulphur of cysteine ) – γ Glutamyl – cysteinyl-Glycine

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Aminoacid metabolism -2

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  1. Aminoacid metabolism -2 Dr. S.Chakravarty MD

  2. Metabolism of Sulphur containing Aminoacids: Metabolic function of cysteine: • Disulphide linkages in Proteins • Formation of Glutathione (functional group is sulphur of cysteine) – γGlutamyl – cysteinyl-Glycine • Active site of many enzymes • Miester cycle – transport of amino acids • Maintain RBCs membrane integrity – Glutathione • Formation ofTaurine– formation of Bile acids and neurotransmitter • Detoxification of drugs - Glutathione –s-transferase

  3. Methionine • Formation of SAM: Methyl Donor Methionine + ATP S-adenosyl Methionine (SAM)

  4. Branched Ch AA Aromatic AA S-containing AA Kaplan step 1 lecture notes

  5. Catabolism of cysteine and methionine Methionine THF ATP Methionineadenosyltransferase S- Adenosyl Methionine (SAM) Acceptor CH3-acceptor Methyl transferase Homocysteine methyl Transferase S- Adenosyl Homocystiene (SAH) B12 Very Important Adenosine Homocysteine Serine Methyl THF B6 (PLP) Cystathionineβsynthase Cystathionine TCA cycle Propionyl Co-A TCA cycle B6 Cystathioninase Pyruvate Cysteine + homoserine Alpha-keto butyrate

  6. Oxidation of odd chain fatty acids • Oxidation of fatty acid with odd no. of carbon atom yields acetyl CoA + Propionyl CoA( Enters TCA as Succinyl Co-A).Thus this portion of odd chain fatty is glucogenic.

  7. Cystinuria : Disorders of sulfur containing aminoacids • Autosomal recessive • Defect in intestine and renal absorption of Cysteine, Ornithine, Lysine, Arginine (COLA) • Cystine stones – hexagonal crystals  Nephrolithiasis and Urolithiasis

  8. Cystinosis • Lysosomal disorder • Defective carrier mediated transport of cysteineIncreased lysosomalcysteine lysosomalcystine appears to amplify and alter apoptosis in such a way that cells die inappropriatelyRenal failure(Fanconi’s syndrome ) • In order of decreasing severity the following are the types of cystinosis:- • nephropathiccystinosis • intermediate cystinosis, • non-nephropathic or ocular cystinosis • Renal failure, vit-D resistant rickets, acidosis, polyuria, photophobia (fanconi syndrome) • Liver, cornea, spleen, kidney, bone marrow involved – crystal formation

  9. Congenital Homocystinuria – Marfanoidhabitus

  10. S-S linkages in Proteins Genetic Defect DIET Homocysteine Homocysteine Thiolactone Lipid peroxidation Activates Hageman factor Oxidized LDL – Endocytosis by Macrophages Platelet aggregation Atherosclerosis

  11. Differences Marfan syndrome Congenital Homocysteinuria Autosomal recessive Lens dislocation is downwards and inwards Ischemic heart disease due to thromboembolic phenomenon Mental retardation common • Autosomal dominant • Lens dislocation is upwards and outwards • Aortic incompetance / valvular heart disease • Mental retardation absent

  12. Acquired Homocysteinuria • Vitamin deficiencies – • B6 • B12 • FOLATE • No Marfanoidhabitus • Reversible • HOW TO DISTINGUISH ? INCREASED HOMOCYSTEINE , INCREASED METHIONINE INCREASED HOMOCYSTEINE DECREASED METHIONINE

  13. Kaplan USMLE step 1 lecture notes SER, GLY x x x MEGALOBLASTIC ANAEMIA WHY MEGALOBLASTS ? When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis (M) stage. This leads to continuing cell growth without division, which presents as macrocytosis.

  14. Accumulation of ODD chain fatty acids in neurons • Toxicity from mehylmalonate Kaplan step 1 lecture notes

  15. Metabolism of Basic amino acids • Histidine : • Imidazole ring – Basic amino acid • Formation of Histamine • Physiological buffer – pKa of 6.8

  16. Metabolism of Histidine Histidine Histidinedecarboxylase Histidase Histamine Urocanate Urocanase histaminase Measure in Folic acid deficiency FIGLU THF Imidazole acetic acid Formimino THF Glutamate Alpha ketoGlutarate TCA cycle FIGLU – formiminoglutamic acid

  17. Histidinemia : • Decreased histidase activity: • Histidine undergoes transamination to form imidazole pyruvate, imidazole lactate and imidazole acetate. • Mistaken for phenylketonuria • Mental retardation • Diagnosis: sweat urocanate levels decreased FIGLU excretion decreased.

  18. 2. Arginine • Formation of urea • Synthesis of Nitric oxide – vasodilator • Synthesis of Creatine phosphate and Creatinine • Synthesis of Polyamines – spermine and spermidine cell growth and proliferartion .

  19. Catabolism of Arginine Arginine Arginase Urea Ornithine Glutamate Alphaketoglutarate TCA cycle

  20. Metabolism of Glycine • Formation of Heme: first step • Formation of Glutathione • Formation of Bile salts – Glycocholic acid • Conjugation – Hippuric acid (Hippuric acid) • C4, C5, N7 of Purine Ring formation

  21. Catabolism of Glycine Primary hyperoxaluria -1 Glycine (-) Ethylene Glycol (Antifreeze) Pyruvate Alanine glyoxylateAminotransferase PLP Alanine Glycolic acid Glyoxylate glyoxylatereductase Certain Sugars and aa Glycolate (-) Primary hyperoxaluria -2 Oxalic acid Calcium oxalate stones

  22. Causes for increased oxalate stone formation • Green leafy vegetables – oxalates • Ascorbic acid – Vit C • Ethylene glycol poisoning – antifreeze • Primary oxaluria – Type 1 and 2 Calcium oxalate stone formation Kidney damage – Renal obstruction

  23. Formation of Creatine and Creatinine Arginine + Glycine Kidney and Pancreas mitochondria Guanidoacetate SAM Diagnosis of various Muscle disorders Liver SAH Creatine CreatinePhosphokinase Urine Creatine phosphate Creatinine

  24. A 56 year old man is being evaluated for macrocyticanaemia. He was severely malnourished.Bothhomocysteine and methyl malonate were elevated in his blood and urine , and the transketolase level in his RBC was low. • What is the best evidence cited that the anaemia is due to B12 deficiency? • A. Macrocyticanaemia • B. Elevated methyl malonate • C. elevated homocysteine • D. decreased homocysteine • E. severe malnutrition

  25. If there is B12 deficiency , which other conditions could develop in such a patient ? • A.peripheral neuropathy • B. Gout • C. Wernicke’sKorsakoff’s syndrome • D. Destructon of parietal cells • E. Bleeding from gums

  26. A 49 year old man has ectopialentis and comes to ER with deep vein thrombosis .He has a normal hematocrit and RBCs are normocyticnormochromic. • A mutation of genes coding for which of the following is the cause ? • A. Cystathionine synthase • B. Homocysteine methyl transferase • C.Fibrillin • D.Lysyloxidase] • E. FACTOR VIII

  27. Amino acid analysis of this patient’s plasma would most likely reveal an abnormally elevated level of • A. Lysine • B.Leucine • C. methionine • D. Ornithine • E. Cysteine

  28. Thank you

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