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18.2 Nitrogen Excretion and the Urea Cycle

18.2 Nitrogen Excretion and the Urea Cycle. Produced in liver. Blood. Kidney  urine. Urea Cycle in Mitochondria. Formation of carbamoyl phosphate; preparatory step NH 4 + + HCO 3 - + 2 ATP  carbamoyl phosphate + 2 ADP + P i Carbamoyl phosphate synthetase I

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18.2 Nitrogen Excretion and the Urea Cycle

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  1. 18.2 Nitrogen Excretion and the Urea Cycle Produced in liver Blood Kidney  urine

  2. Urea Cycle in Mitochondria • Formation of carbamoyl phosphate; preparatory step NH4+ + HCO3- + 2 ATP  carbamoyl phosphate + 2 ADP + Pi Carbamoyl phosphate synthetase I - ATP-dependent reaction • 1st step in the urea cycle; Ornitine + carbamoyl phosphate  citrulline + Pi Ornitine transcarbamoylase

  3. Urea Cycle in Cytosol • 2nd step; formation of argininosuccinate Incorporation of the second N from aspartate Argininosuccinate synthetase • ATP requirement • Citrullyl-AMP intermediate • 3rd step; formation of arginine & fumarate Arginosuccinase; only reversible step in the cycle • 4th step; Cleavage of arginine to urea & ornithine Arginase

  4. Asparatate-argininosuccinate shunt • Metabolic links between citric acid and urea cycles • In cytosol • Fumarate to malate  citric acid cycle in mitochondria • In mitochondria • OAA + Glu  a-ketoglutarate + Asp  urea cycle in cytosol • Energetic cost • Consumption • 3 ATP for urea cycle • Generation • Malate to OAA • 1 NADH = 2.5 ATP

  5. Regulation of the Urea Cycle • Long term regulation • Regulation in gene expression • Starving animals & very-high protein diet • Increase in synthesis of enzymes in urea cycle • Short term regulation • Allosteric regulation of a key enzyme • Carbamoyl phosphate synthetase I • Activation by N-acetylglutamate

  6. Treatment of genetic defects in the urea cycle • Genetic defect in the urea cycle •  ammonia accumulation; hyperammonemia • Limiting protein-rich diet is not an option • Administration of aromatic acids; benzoate or phenylbutyrate • Administration of carbamoyl glutamate • Supplement of arginine

  7. 18.3 Pathways of Amino Acid Degradation

  8. Amino Acid Catabolism • Carbon skeleton of 20 amino acids • Conversion to 6 major products - pyruvate - acetyl-CoA - a-ketoglutarate - succinyl-CoA - fumarate - oxaloacetate

  9. Glucogenic or Ketogenic Amino Acids • Ketogenic amino acids • Conversion to acetyl-CoA or acetoacetyl-CoA  ketone bodies in liver • Phe, Tyr, Ile, Leu, Trp, Thr, Lys • Leu : common in protein • Contribution to ketosis under starvation conditions • Glucogenic amino acids • Conversion to pyruvate, a-ketoglutarate, succinyl-CoA, fumarate, and OAA  glucose/glycogen synthesis • Both ketogenic and glucogenic • Phe, Tyr, Ile, Trp, Thr

  10. Enzyme cofactors in amino acid catabolism • One-carbon transfer reactions ; common reaction type, involvement of one of 3 cofactors • Biotin ;one-carbon tranfer of most oxidized state, CO2 • Tetrahydrofolate (H4 folate) ;One-carbon transfer of intermediate oxidation states or methyl groups • S-adenosylmethionine ; one-carbon transfer of most reduced state, -CH3

  11. Tetrahydrofolate • folate (vitamin) to H4 folate • Dihydrofolate reductase • Primary source of one-carbon unit • Carbon removed in the conversion of Ser to Gly • Oxidation states of H4 folate ; One-carbon groups bonded to N-5 or N-10 or both - Methyl group (most reduced) - Methylene group - Methenyl, formyl, formimino group (most oxidized) • Interconvertible & donors of one-carbon units (except N5-methyl-tetrahydrofolate)

  12. S-adenosylmethionine (adoMet) • Cofactor for methyl group transfer • Synthesized from Met and ATP • Methionine adenosyl transferase • Unusual displacement of triphosphate from ATP • Potent alkylating agent • Destabilizing sulfonium ion  inducing nucleophilic attack on methyl group

  13. Six amino acids are degraded to pyruvate • Ala, Trp, Cys, Ser, Gly, Thr •  pyruvate   acetyl-CoA  citric acid cycle or gluconeogenesis

  14. Interplay of PLP and H4folate in Ser/Gly metabolism

  15. 3rd pathway of glycine degradation • - D-amino acid oxidase • detoxification of D-amino acid • high level in kidney • - Oxalate  crystals of calcium oxalate (kidney stones)

  16. Seven Amino Acids Are Degraded to Acetyl-CoA • Trp, Lys, Phe, Tyr, Leu, Ileu, Thr  acetoacetyl-CoA  acetyl-CoA

  17. Intermediates of Trp catabolism be precusors for other biomolecules

  18. Catabolic pathways for Phe & Tyr • Phe & Tyr are precusors • dopamine • norephinephrine, epinephrine • melanin

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