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Amino acid metabolism ·        Nitrogen balance protein catabolism,

Amino acid metabolism ·        Nitrogen balance protein catabolism, synthesis biosynthesis normal N balance: N ingested = N excreted negative N balance: N ingested < N excreted positive N balance: N ingested > N excreted. (NH 4 + . urea).

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Amino acid metabolism ·        Nitrogen balance protein catabolism,

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  1. Amino acid metabolism ·        Nitrogen balance protein catabolism, synthesis biosynthesis normal N balance: N ingested = N excreted negative N balance: N ingested < N excreted positive N balance: N ingested > N excreted (NH4+. urea) Dietary protein amino acid pool N excretion

  2. Requirement for essential amino acids

  3. Amino acid catabolism • ·        accounts for ~ 10% of energy requirement of adults • ·       When: • ·       excess protein in diet (amino acids are not stored) • ·        protein degradation exceeds demand for new protein • ·        starvation when carbohydrates are not available • ·        (protein storing seeds such as beans, peas, etc.) • ·      

  4. Glucogenic vs ketogenic amino acids ·       ketogenic: yield AcCoA or AcAc as end products of catabolism - leu, lys ·       glucogenic: are degraded to pyruvate or a member of the TCA cycle (succinylCoA, OAA, a-ketoglutarate, fumarate). In absence of sugars, glucogenic amino acids permit continued oxidation of fatty acids by maintaining TCA cycle intermediates. Also source of carbons for gluconeogenesis in liver - ile, phe, tyr, trp ·        glucogenic and ketogenic: yield both ketogenic and glucogenic products. - all others

  5. 2 1 4 N catabolism General strategy: ·     removal of N from amino acid by transamination (generally first or second step of amino acid catabolic pathways) and ·        collection of N in glutamic acid ·        deamination of glutamic acid with release of NH4+ -glutamate dehydrogenase 3. Collection of N in glutamine or alanine for delivery to liver ·removal of NH4+ by : i. secretion; or ii. conversion to urea or other less toxic form.

  6. to e-amino of lysine Vitamine B6 family Pyridoxine Pyridoxal Pyridoxamine Pyridoxal phosphate See Horton: page 212 section 7.7 pyridoxal phosphate

  7. 1. Transamination reaction R1 H- C-NH3+ COO- see text p 537 and fig 17.7. Lys-protein NH + a-aminoacid-1 Schiff base with enzyme R1 H-C-COO- Lys-protein NH Schiff base with substrate

  8. R1 H- C- COO- R1 H-C-COO- Lys-protein NH Schiff base with substrate Lys-protein NH2 O + a-ketoacid-1 Pyradoxamine phosphate

  9. R2 H-C-COO- Lys-protein NH2 Lys-protein NH O + a-ketoacid-2 R2 H- C- COO-

  10. R2 H- C-NH3+ COO- R2 H-C-COO- Lys-protein NH Lys-protein NH + a-amino acid-2

  11. Net reaction: e.g. alanine + a-ketoglutarate pyruvate + glutamate a-amino acid-1 + a-ketoacid-2 PLP a-amino acid-2 + a-ketoacid-1

  12. 2 1 4 N catabolism General strategy: ·     removal of N from amino acid by transamination (generally first or second step of amino acid catabolic pathways) and ·        collection of N in glutamic acid ·deamination of glutamic acid with release of NH4+ -glutamate dehydrogenase 3. Collection of N in glutamine or alanine for delivery to liver ·removal of NH4+ by : i. secretion; or ii. conversion to urea or other less toxic form.

  13. 2. glutamate dehydrogenase (see p 533 for reaction) • - release or capture of NH4+ • ·        - located in mitochondria • ·        - operates near equilibrium NAD NADH glutamate + H2O a-ketoglutarate + NH4+ NADP NADPH amino acid + a-ketoglutar a-keto acid + glutamate glutamate + NAD + H2O a-ketoglutar +NADH + H+ + NH4+ amino acid + NAD + H2O a-keto acid +NADH + H+ + NH4+

  14. 3. transport of N to the liver - glutamine synthetase - glutaminase - alanine/glucose cycle 1. Glutamine synthetase ATP ADP + Pi glutamate + NH4+ glutamine 2. Glutaminase glutamine glutamate + NH4+ Note: glutamate can be used for glucose synthesis. How? • Formation of alanine by transamination: • alanine/glucose cycle

  15. Alanine-glucose cycle Muscle glucose 2 pyruvate 2 a-aa 2 a-ka 2 alanine 2 alanine glucose Liver glucose 2 pyruvate 2 Glu 2 a-kG 2 NH4+ 2 alanine

  16. Pyr Glucose Ala 2NH4+ 2NH4+ 2Glu 2Glu’NH2 2a-KG Glu’NH2 Glu a-KG 4CO2 Glucose NH4+ KIDNEY HCO3 + H+ H2CO3 CO2 H2O MUSCLE NH4+ Glu’NH2 energy Pyr Glu a-ka protein Glucose a-aa Ala a-KG CO2 Urea LIVER Urea

  17. Urea cycle Where: Liver: mito/cyto Why: disposal of N Immediate source of N: glutamate dehydrogenase glutaminase Fate of urea: liver kidney urine How much: ~ 30g urea / day

  18. NH4+ + HCO3- + 2 ATP H2N-C-OPO3-2 + Pi + 2 ADP O 2. Ornithine transcarbamylase (mito) Pi carbamyl phosphate ornithine citrulline Reactions of urea cycle 1. Carbamyl phosphate synthetase I (mito) carbamyl phosphate • committed step • by N’Ac glutamate

  19. 4. Arginosuccinate lyase (cyto) + fumarate arginine 3. Arginosuccinate synthetase (cyto) + AMP + PPi ATP arginosuccinate

  20. 5. Arginase (cyto) urea ornithine

  21. NH3+ aKG 2ATP HCO3 2ADP +Pi NADH + H+ NAD ornithine asparate glutamate MITO CYTO ornithine citrulline asparate glutamate ATP AMP + PPi fumarate See fig 17.26

  22. Interorgan relationships in N metabolism Epithelial cells of intestine Several steps Glu’NH2 cittruline Glu’NH2 Glu’NH2 Liver Kidney cittruline Arg Arginine Arginine Urea cycle Several steps Urea Ornithine 2 steps creatine glutamate To urine Muscle creatine P-creatine Several steps creatinine Adapted from Devlin, Biochemistry with Clinical Corrleation 4th ed.

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