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Ammonia production and toxicity ط      Transport of ammonia , toxicity

Ammonia production and toxicity ط      Transport of ammonia , toxicity ط      Amino acid oxidase reaction ط      Ammonia transport to liver and kidney ط      Intracellular glutamine cycle                                            D4   452 -56 . Ammonia Production.

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Ammonia production and toxicity ط      Transport of ammonia , toxicity

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  1. Ammonia production and toxicity ط     Transport of ammonia , toxicity ط     Amino acid oxidase reaction ط     Ammonia transport to liver and kidney ط     Intracellular glutamine cycle                                            D4   452 -56 

  2. Ammonia Production • a) fig11.11, α-Keto/Amino Acid Cycle • α-KG GltDH (–NH4+/NADPH)  Glt • fig11.13, ammonia incorporation is stimulated by ATP/GTP • Glt GltDH (+NH4+/NADH)  α-KG • fig11.13, ammonia release is stimulated by ADP/GDP • b) fig11.14 – 11.15, Glutamine Cycle • Glt  Glt Synthetase (–NH4+/ATP)  Gln (carrier of ammonia) • Gln  Glt-ase (+NH4+)  Glt (ammonia released)

  3. Ammonia Production Release of Amonia by Other Reactions • c) fig11.19, Oxidative Deamination (L-AA) • α-Amino Acid AA Oxidase (–FMN/ +H2O2) α-Imino Acid Deamination (+NH3)  α-Keto Acid • D-AA oxidase by intestinal bacteria • d) fig, Non Oxidative Deamination • Serine Ser DH è a-Imino Acid Deamination (+NH3)  Pyruvic Acid • e) fig, Amino Desulfhydration • Cystein Cys DS a-Imino Acid Deamination (+NH3)  Pyruvic Acid • f) fig, Amino Decarboxylation • · Histidine His Decarboxylase (–CO2)  Histamine • · Serine Ser Decarboxylase (–CO2)  Ethanolamine • * Ammonia released in kidney is excreted • * Ammonia released in liver can be used to produce urea

  4. Ammonia production and toxicity  Urea cycle ط     Urea cycle : steps and regulation ط     Transport and excretion of urea ط     Clinical correlation:                                     Metabolic disorders of urea synthesis                                     Deficiency of urea cycle enzymes                                            D4 452 -56 

  5. Urea Cycle Urea cycle is the mechanism of nitrogen excretion fig11.21, 1 nitrogen form Ammonia and 1 nitrogen from Asp

  6. Reactions of Urea Cycle • fig11.22 – 11.24, synth in liver: • In Mitoch:  HCO3– + ATP CPS-ase 1 (+ADP)  HCO3–P • HCO3–P + Ammonia CPS-ase 2 (–ATP)  Carbomyl Phosphate (1N) • Carbomyl Phspahte (1N) + Ornithine (2N) OTC-lase Citrulline (3N) • In Cyto:   Citruline (3N) + Aspartate ASS-tase (–ATP)  Argininosuccinate (4N) • Argininosuccinate AS lyase Arginin (4N) + Fumarate (to OA to PEP) • Arginine (4N) Arginase Ornothine (2N) + Urea (2N) • In Cyto:          Citruline (3N) + Aspartate ASS-tase (–ATP)  Argininosuccinate (4N)

  7. Reactions of Urea Cycle Ammonia (NH4+) is released from Gln Glt can be transferred to Ornithine fig11.23, CPS-ase 1 is activated by Acetyl Glutamate ACoA + Glt è AG S-tase è AG AG S-tase is activated by Arg * Urea transported to kidneys are excreted * but if transported to intestine it will under go bacterial urease releasing ammonia, which returns to liver

  8. Clinical Correlation * Ammonia is very toxic causing decrease in ATP that leads to coma * High ammonia lead to α-KG to form Glt (leave TCA cycle, no energy) * Deficiencies in each enzyme of urea cycle are found and treated by 1.        Limit prt intake: decrease AA and increase α-KG in diet acidify colon by Levuloase to decrease AA absorbance use antibiotic to reduce bacterial transamination 2.        Remove excess ammonia use compounds that bind to nitrogen and excreted in urine (need CoA/ATP) 3.        Replace urea cycle intermediates

  9. Clinical Correlation Metabolic Disorder of urea synthesiscc11.1 Hyperammonemia causes mental retardation due to: 1.        Deficiency in CPS can be treated by limiting prt intake (as above) or addition of arg (activates AG S-tase) to activate CPS-ase 2.        Deficiency in AG S-tase treated by Carbomyl Glt (analogue of AG) to activate CPS-ase

  10. Clinical Correlation Deficiency of urea cycle enzymescc11.2 Hyperammonemia causes mental retardation due to: 1.        Deficiency in Orn T C-lase Most common deficiency and in male more than female Lead to mental retardation & death Carbomyl Phosphate + Asp è orate (orotic acid) 2.        Deficiency in Arg S S-tase Lead to citrullinemia, high citrulline in blood & urine Treated with arg (arg => prt => creatine) 3.        Deficiency in Arg Lyase Lead to increase of Argininosuccinate in urine Treated with arg (complete the cycle) 4.        Deficiency in Arg-ase Rare but cause abnormalities in CNS High arg lead to excretion Treated with EAA, but no arg

  11. Catabolism of carbon skeleton of amino acids ط      Ketogenic and Glucogenic amino acids ط     Metabolic fate of some amino acids ط     Site of entry into intermediates of CAC L2 526 -36  Amino Acids as Carbon Source ·         Table7.2, AAs are divided into ketogenic AAs & glucogenic AAs or both ·         Keto-AA cannot function as C source ·         fig11.2, Whereas Glc-AAs do, and enter the carbon skeleton in 7 points

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