Metabolism of Sulfur Containing Amino Acids (Methionine, Cysteine, Cystine)
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Metabolism of Sulfur Containing Amino Acids (Methionine, Cysteine, Cystine)
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Metabolism of Sulfur Containing Amino Acids (Methionine, Cysteine, Cystine)
- 2. 2 of 58 Metabolism of Sulfur Containing Amino acids Ashok Katta Sulfur Containing Amino acids Cystine Cysteine Methionine
- 3. Methionine cysteine Protein Glucose Glucose Glutathione Taurine Coenzyme A Active sulfate cystine Initiation of protein biosynthesis Transmethylation Cystathionine Polyamines
- 5. Sulfur containing A.A. Aliphatic AA. Neutral AA. α-amino γ thiomethyl butryic acid. Essential AA. Glucogenic AA. H I NH2- C α - COOH I CH2 I CH2 γ I S - CH3 THIOETHER
- 6. Proteins Glucose Cysteine by trans-sulfuration S-adenosyl Methionine (SAM) Compounds formed -
- 7. PROTEIN SYNTHESIS Methionine is coded by codon AUG. This codon is called start codon. Methionine is first amino acid used to build a protein chain.
- 9. Formation of Active Methionine H I NH2-C-COOH I CH2 I CH2 I S -CH3 H I NH2-C -COOH I CH2 I CH2 I +S ~CH3 I AdenosylMethionine S-adenosyl methionine (SAM) Stable CH3 group Labile CH3 group 3 ATP are used Sulfonium atom SAM is more commonly used for CH3 transfer. ATP PPi + Pi S-Adenosylmethionine synthetase
- 11. S-adenosyl Methionine S-adenosyl homocysteine Norepinephrine Guanidoacetate N-acetyl serotonin Phosphatidyl ethanolamine Ethanolamine Nicotinamide t-RNA Histidine Carnosine Lysine Epinephrine Creatine Melatononin Phosphatidyl Choline Choline N-methyl Nicotinamide Methylated t-RNA N-methyl histidine Anserine Trimethyl lysine Methyl group ACCEPTOR Methylated Products
- 12. Methionine S-Adenosylmethionine (SAM) S-Adenosylmethionine synthetase ATP Pi + PPi 2 Pi S-Adenosylhomocysteine (SAH) Methyltransferase Methylated products Methylated acceptors L-Homocysteine H2O Adenosine B12 Methyl B12 Methyl THF THF Regeneration of Methionine Homocysteine Methyl Transferase
- 13. Importance of Transmethylation - Biologically Significant – many compounds become functionally active only after Methylation . Protein Methylation – helps to control protein turn over. Methylated proteins – less degraded. SAM – precursor for – Ethylene – plant hormone –growth , ripening of fruits.
- 16. Enzymes involved in formation and utilization of S-adenosylmethionine are particularly active in liver. Liver has important roles in synthetic pathways involving methylation reactions, & in regulation of blood methionine.
- 17. Conversion of Methionine to Cysteine 1. Formation of S-adenosyl Methionine . 2. Formation of S-adenosyl Homocysteine. 3. Formation of Homocysteine. 4. Formation of Cysteine.
- 18. Methionine S-Adenosylmethionine (SAM) S-Adenosylmethionine synthetase ATP Pi + PPi 2 Pi S-Adenosylhomocysteine (SAH) Methyltransferase Methylated products Methylated acceptors L-Homocysteine H2O Adenosine B12 Methyl B12 Methyl THF THF Regeneration of Methionine Homocysteine Methyl Transferase
- 19. L-Homocysteine Cystathionine-β- synthase L-Serine H2O Cystathionine Cystathionase L- Cysteine +Homoserine Deamination α - ketobutarate Propionyl-Co A Succinyl Co A Glucose
- 21. Major fate of cystine is conversion to Cysteine catalysed by cystine reductase. Catabolism of Cystine Cystine reductase 2H+ Cystine Cysteine
- 23. Cysteine is … Aliphatic AA, Sulfur containing AA. Non-essential AA. glucogenic AA. α-amino β mercapto pyruvic acid.
- 24. Synthesis of Cysteine Cysteine is synthesized from 2 amino acids… Methionine and Serine
- 25. Methionine S-Adenosylmethionine (SAM) S-Adenosylmethionine synthetase ATP Pi + PPi Methylated products S-Adenosylhomocysteine (SAM) Homocysteine Cystathionine Cysteine Methyltransferase Cystathionine β- synthase Methyl acceptors Adenosine H2O H2O Serine Ketobutyrate + NH4 + H2O Cystathionase
- 26. Cysteine can be catabolised in two way… Transamination pathway Direct oxidative pathway
- 27. Transamination pathway Cysteine β-mercaptopyruvate Cysteine transaminase α-ketoglutarate L-Glutamate Pyruvate H2S Sulfide Sulfite Sulfate PAPS Active Sulfate Excreted in urine Desulfuration Reduced glutathione ATP
- 28. Direct Oxidative Pathway Cysteine Cysteine sulfinate Cysteine dioxygenase O2 CO2 hypotaurine Taurine β-Sulfinyl pyruvate Sulfate PAPS Active Sulfate Pyruvate Decarboxylation Oxidation Desulfuration Pyruvate Alanine ATP
- 29. Importance of Cysteine Glucogenic Dietary source of Sulfur Taurine physiologically important S-containing compounds derived from cysteine are… Insulin, Vasopressin Glutathione Co-enzyme –A PAPS De-toxification
- 31. Metabolic disorders of Cysteine Cystinuria – It is the most common inborn error of AA transport. Autosomal Recessive DEFECT- Impaired Reabsorption of Cystine, Ornithine, Arginine, Lysine (COAL) This is characterised by urinary excretion of these AAs.
- 32. Clinical findings Cystine – (least soluble) insoluble in water Cystine renal stones. Usually its benign condition. Lead to obstruction, infection, renal insufficiency Renal Failure, Hypertension.
- 33. Treatment ↑ Fluid intake. Alkalinise urine by oral HCO3. D-Penicillamine – complexes with cystine , makes water-soluble.
- 34. Rare but serious lysosomal disorder. Genetic: An autosomal recessive defect. Incidence : 1 in 100,000 to 200,000 newborns. Defect: Carrier that transports Cystine across lysosomes to cytosol, The net outcome: Cystine crystals accumulates in Lysosomes of many tissues, like Kidney, Cornea, Lens. Leads to: functions of those tissues impaired and also generalised Aminoaciduria . Δ – Cystine crystals in Leukocytes.
- 36. Hypermethionemia – Impaired utilization Excessive remethylation of homocysteine Hepatic dysfunction. Inherited Deficiency of L-methionine adenosyl transferase. ↑ Plasma Methionine levels.
- 37. Homocystinurias are a group of disorder of methionine metabolism. Genetic: An autosomal recessive defect. Incidence : About 1 in 2,00,000 births. It is characterized by high blood and urinary levels of homocysteine and methionine. Four metabolic defects cause four types of homocystinuria.
- 38. Types of Homocystinuria There are four types of Homocystinuria…. Types Defect Homocystinuria-I Cystathionine β synthase Homocystinuria-II N5,N10 methylene THF reductase Homocystinuria-III N5,N10 - Methyl THF homocysteine methyltransferase (leads to defect in synthesis of methylcobalamin ) Homocystinuria-IV Defect intestinal absorption of vitamin B12
- 39. Enzyme defect: Cystathionine β synthase. The net outcome: homocysteine & methionine accumulates in blood and appears in urine. Leads to: Accumulation of homocysteine causes… Skeletal abnormalities (Osteoporosis , kyphosis), ectopia lentis (dislocation of the lenses in the eyes), Mental retardation and Thrombosis ( platelet adhesiveness). Thrombosis may result in myocardial infarction, pulmonary embolism or stroke. H o m o c y s t i n u r i a - I
- 40. Clinical findings- Cyanide – nitroprusside test - +ve. Guthrie test for Methionine Plasma Homocysteine, Methionine. Cysteine. Homocysteine in urine – overflow aminoaciduria. Activity of Cystathionine –synthase Rx – Diet – low in Methionine. rich in Cysteine. B6.
- 41. Enzyme defect: N5,N10 methylene THF reductase. The net outcome: N5,N10 methylene THF can not covert into N5 methyl THF. Leads to: methionine can not converts to homocysteine. Accumulation of homocysteine. H o m o c y s t i n u r i a - I I
- 42. Enzyme defect: N5,N10- Methyl THF homocysteine methyltransferase. The net outcome: Defect in synthesis of a active form of cobalamin Leads to: Methionine can not converts to homocysteine. Accumulation of homocysteine & excretion in urine. Rx- Folate, Meth . in Diet . B12 , Meth . In diet . H o m o c y s t i n u r i a - I I I
- 43. Defect: Intestinal absorption of vitamin B12. Leads to: Methionine can not converts to homocysteine. Accumulation of homocysteine & excretion in urine. Rx- Folate, Meth . in Diet . B12 , Meth . In diet . H o m o c y s t i n u r i a - I V
- 44. risk of C.A.D Homocysteine binds Copper , inhibits Lysyl oxidase - of collagen – interferes with cross-linking . Thrombosis – activation of Hageman’s factor - platelet adhesiveness. Forms Homocysteine thiolactone , thiolates LDL – aggregate , taken up by macrophages , atherosclerosis - risk of C.A.D.
- 45. 3. Cystathioninuria Cystathioninase – absent A. Recessive C/F – Mental Retardation anaemia, – Thrombocytopenia . ∆ - Cystathionine in urine , - Negative nitroprusside test . Rx- high amount of B6 . Acquired – B6 deficiency.
- 46. ….