Amino-Acid Metabolism [Methionine].pptx..

Amino acid

1. Methionine

2. Methionine Sulfur containing Essential

3. Metabolism of methionine Utilization for trans-methylation reactions Conversion to cysteine and cystine Degradation of cysteine Metabolism

4. Trans-methylation Transfer of methyl group (–CH 3 ) from active methionine to an acceptor Active methionine: SAM (S-Adenosyl-Methionine) Utilization for trans-methylation reactions

5. Synthesis of SAM By the transfer of an Adenosyl group from ATP to sulfur atom of methionine Catalyzed by Methionine S-Adenosyl Transferase Metabolism Utilization for trans-methylation reactions

6. Synthesis of SAM Sulfur of methionine becomes “ Sulfonium ” [SAM is a Sulfonium compound] All three phosphates are removed as PPi + Pi; PPi is further hydrolyzed to 2Pi (pyrophosphatase) Energy utilization: equivalent to 3 ATP Metabolism Utilization for trans-methylation reactions

7. Functions of SAM SAM: Highly reactive (presence of a positive charge) Trans-methylation reactions: Methyl Transferases SAM transfers methyl group to an acceptor and itself gets converted to SAH (S-Adenosyl Homocysteine) Metabolism Utilization for trans-methylation reactions

8. Regeneration of Methionine SAH is hydrolyzed to adenosine and homocysteine Homocysteine is re-methylated to methionine (methyl donor: N 5 -Methyl THF) Metabolism Utilization for trans-methylation reactions

9. Synthesis of cysteine Homocysteine: precursor for cysteine synthesis; condenses with serine to form cystathionine ( cystathionine synthase ) Cystathionine undergoes (cleavage + deamination) to form Cysteine + alpha– keto butyrate ( cystathioninase ) Trans-sulfuration reactions Metabolism Conversion to Cysteine and Cystine

10. Degradation of Cysteine Cysteine and Cystine are interconvertible (cysteine reductase; NAD+-dependent) Decarboxylation: mercapto-ethanolamine (biosynthesis of CoA from vitamin pantothenic acid) Oxidation: Cysteine sulfinate Degradation: H 2 S + NH 3 + Pyruvate (Desulfhydrase) Metabolism Further Metabolism of Cysteine

11. Degradation of Cysteine ( cysteine sulfinate) Further oxidized to Cysteic acid Decarboxylation – taurine (conjugation with bile acids); Degradation – pyruvate (glycogenic) Cleavage to (Alanine + Sulfite) Sulfite – Sulfate (excreted in urine) Some amount of sulfate + ATP – Active sulfate (PAPS) PAPS (3’-phosphoadenosine 5’-phosphosulfate) – Synthesis of MPS and detoxification Metabolism Further Metabolism of Cysteine

12. Clinical Correlation Homocysteine and cardiovascular diseases Inborn errors Cystinuria C ystinosis Homocysteinuria Metabolism Applied Aspects

13. Homocysteine An intermediate in the synthesis of cysteine from methionine Plasma levels > 15 micro-mol/L implicated in coronary artery diseases High levels in pregnancy – increased risk of neural tube defects in fetus Metabolism Homocysteine and cardiovascular diseases

14. Homocysteine Possible mechanisms of CAD Reacts with collagen – produces reactive free radicals + interferes with collagen cross-linking Aggregation of LDL particles (LDL is abnormally modified) Resultant increased tendency of atherosclerosis and thus, CAD Metabolism Homocysteine and cardiovascular diseases

15. Homocysteine To lower plasma levels Beneficial role of dietary supplementation of Folic acid Vitamin B 12 and Vitamin B 6 Metabolism Homocysteine and cardiovascular diseases

16. Cystinuria (Cystine – Lysinuria) One of the commonest inherited diseases (frequency – 1:7000) Increased excretion of cystine (25-40 times normal) Defect Defective specific carrier system (single) for renal tubular reabsorption of Cystine, Ornithine, Arginine, and Lysine Increased excretion of C ysteine with O rnithine, A rginine , L ysine (COAL) Metabolism Inborn Errors

17. Cystinuria (Cystine – Lysinuria) Consequence Precipitation of cystine and formation of cystine stones in kidney and urinary tract (cystine is relative insoluble) Laboratory test Cyanide nitroprusside test Treatment Restricted ingestion of dietary cysteine High intake of fluids Metabolism Inborn Errors

18. Cystinosis (cystine storage disease) D efect Defective Lysosomal function (accumulation of cystine in the lysosomes) Defective Cystine Reductase has also been implicated Metabolism Inborn Errors

19. Cystinosis (cystine storage disease) Consequences Deposition of cystine crystals in tissues and organs, especially of RES (spleen, lymph nodes, liver, kidney, bone marrow, etc) Impairment of renal function – generalized amino acidurias Survival beyond 10 years of age (rare) – death due to renal failure commonly Metabolism Inborn Errors

20. Homocystinurias A group of metabolic disorders characterized by the accumulation and increased urinary excretion of Homocysteine and SAM Plasma concentration of methionine is also increased Types Homocystinuria type I Homocystinuria type II Homocystinuria type III Metabolism Inborn Errors

21. Homocystinuria type I Defective enzyme Cystathionine Synthase Complications Accumulated homocysteine: Thrombosis; Osteoporosis; Mental retardation Deficiency of cystathionine: Damage to endothelial cells – atherosclerosis Metabolism Inborn Errors

22. Homocystinuria type I Defective enzyme Cystathionine Synthase Two forms B 6 responsive: Corrected with vitamin B6 supplementation B 6 non-responsive: Not corrected with vitamin B 6 supplementation (t/t: dietary restriction of methionine and inclusion of cystine) Metabolism Inborn Errors

23. Homocystinuria type II Defective enzyme: N5-N10 – Methylene THF Reductase Homocystinuria type III Defective enzyme: N5-N10-Methyl THF Homocysteine Methyl Transferase Impaired synthesis of Methyl-Cobalamin Homocystinuria type IV Defective enzyme: N5-Methyl THF Homocysteine Methyl Transferase Defective intestinal absorption of Vitamin B 12 Metabolism Inborn Errors