Amino Acid Catabolism 2

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Amino Acid Catabolism 2

  1. 1. Amino Acid Catabolism Disposal of Nitrogen and Carbon Skeletons
  2. 2. Overview of Amino Acid Catabolism: Interorgan Relationships <ul><li>Intestine </li></ul><ul><ul><li>Dietary amino acids absorbed </li></ul></ul><ul><ul><li>Utilizes glutamine and asparagine as energy sources </li></ul></ul><ul><ul><ul><li>Releases CO 2 , ammonium, alanine, citrulline as endproducts </li></ul></ul></ul><ul><ul><ul><li>Utilizes glutamine during fasting for energy </li></ul></ul></ul><ul><ul><li>Dietary amino acids and catabolites released to portal blood </li></ul></ul>
  3. 3. Enteral Formulas containing glutamine <ul><li>JUVEN is a therapeutic nutritional that contains a patented blend of arginine, glutamine, and HMB (beta-hydroxy-beta-methylbutyrate). JUVEN has been clinically shown to help build lean body mass (LBM), 1,2 enhance immune response, 2 and promote collagen synthesis </li></ul>
  4. 4. Overview of Amino Acid Catabolism: Interorgan Relationships
  5. 5. Overview of Amino Acid Catabolism: Interorgan Relationships <ul><li>Liver </li></ul><ul><ul><li>Synthesis of liver and plasma proteins </li></ul></ul><ul><ul><li>Catabolism of amino acids </li></ul></ul><ul><ul><ul><li>Gluconeogenesis </li></ul></ul></ul><ul><ul><ul><li>Ketogenesis </li></ul></ul></ul><ul><ul><ul><li>Branched chain amino acids not catabolized </li></ul></ul></ul><ul><ul><ul><li>Urea synthesis </li></ul></ul></ul><ul><ul><li>Amino acids released into general circulation </li></ul></ul><ul><ul><ul><li>Enriched in BCAA (2-3X) </li></ul></ul></ul>
  6. 6. Overview of Amino Acid Catabolism: Interorgan Relationships
  7. 7. Overview of Amino Acid Catabolism: Interorgan Relationships <ul><li>Skeletal Muscle </li></ul><ul><ul><li>Muscle protein synthesis </li></ul></ul><ul><ul><li>Catabolism of BCAA </li></ul></ul><ul><ul><ul><li>Amino groups transported away as alanine and glutamine (50% of AA released) </li></ul></ul></ul><ul><ul><ul><ul><li>Alanine to liver for gluconeogenesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Glutamine to kidneys </li></ul></ul></ul></ul><ul><li>Kidney </li></ul><ul><ul><li>Glutamine metabolized to a-KG + NH 4 </li></ul></ul><ul><ul><ul><li>a-KG for gluconeogenesis </li></ul></ul></ul><ul><ul><ul><li>NH 4 excreted or used for urea cycle (arginine synthesis) </li></ul></ul></ul><ul><ul><ul><ul><li>Important buffer from acidosis </li></ul></ul></ul></ul>
  8. 8. Overview of Amino Acid Catabolism: Interorgan Relationships
  9. 9. Vitamin-Coenzymes in Amino Acid Metabolism <ul><li>Vitamin B-6 : pyridoxal phosphate </li></ul><ul><ul><li>Enzymes that bind amino acids use PLP as coenzyme for binding </li></ul></ul><ul><ul><ul><li>Transaminases </li></ul></ul></ul><ul><ul><ul><li>Amino acid decarboxylases </li></ul></ul></ul><ul><ul><ul><li>Amino acid deaminases </li></ul></ul></ul>
  10. 10. Vitamin-Coenzymes in Amino Acid Metabolism <ul><li>Folacin: Tetrahydrofolate (THF) </li></ul><ul><ul><li>Carrier of single carbons </li></ul></ul><ul><ul><ul><li>Donor & receptor </li></ul></ul></ul><ul><ul><ul><li>Glycine and serine </li></ul></ul></ul><ul><ul><ul><li>Tryptophan degradation </li></ul></ul></ul><ul><ul><ul><li>Histidine degradation </li></ul></ul></ul><ul><ul><ul><li>Purine and pyrimidine synthesis </li></ul></ul></ul>
  11. 11. Vitamin-Coenzymes in Amino Acid Metabolism <ul><li>Vitamin B-12 </li></ul><ul><ul><li>Catabolism of BCAA </li></ul></ul><ul><ul><ul><li>Methyl-malonyl CoA mutase (25-9 &10) </li></ul></ul></ul>
  12. 12. Vitamin-Coenzymes in Amino Acid Metabolism <ul><li>Vitamin B-12 </li></ul><ul><ul><li>Methionine synthesis/recycling </li></ul></ul><ul><ul><ul><li>Methionine as a methyl donor </li></ul></ul></ul><ul><ul><ul><ul><li>Choline and creatine synthesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Homocysteine is product </li></ul></ul></ul></ul><ul><ul><ul><ul><li>HCys -> Met requires B-12 </li></ul></ul></ul></ul>
  13. 13. Disposal of Amino Groups: Transamination Reactions <ul><li>Generally the first step of amino acid degradation </li></ul><ul><li>Transfer of amino group from many amino acids to limited number of keto acid acceptors </li></ul><ul><ul><li>Pyruvate -> alanine </li></ul></ul><ul><ul><li>Oxaloacetate -> aspartate </li></ul></ul><ul><ul><li>Alpha-keto-glutarate -> glutamate </li></ul></ul>
  14. 14. Disposal of Amino Groups: Transamination Reactions <ul><li>Transamination reactions tend to channel amino groups on to glutamate </li></ul><ul><ul><li>Glutamate’s central role in amino acid N metabolism </li></ul></ul>
  15. 15. Disposal of Amino Groups: Transamination Reactions <ul><li>Transaminase reactions are reversible </li></ul><ul><ul><li>ALT = SGOT </li></ul></ul><ul><ul><ul><li>ALA important in muscle where ~25% of AA-N is transported out on ALA </li></ul></ul></ul><ul><ul><ul><li>In liver, reverse reaction moves AA-N back on GLU </li></ul></ul></ul><ul><ul><li>AST = SGPT </li></ul></ul><ul><ul><ul><li>ASP important in liver since half of urea-N is from ASP </li></ul></ul></ul>
  16. 16. Disposal of Amino Groups: Deamination Reactions <ul><li>Glutamate dehydrogenase </li></ul><ul><ul><li>oxidative deamination </li></ul></ul><ul><ul><li>Important in liver where it releases ammonia for urea synthesis </li></ul></ul><ul><li>Hydrolytic deamination </li></ul><ul><ul><li>Glutaminase & asparaginase </li></ul></ul>
  17. 17. Disposal of Amino Groups: Glutamine Synthetase <ul><li>Important plasma transport form of nitrogen from muscle </li></ul><ul><li>Detoxification of ammonia </li></ul><ul><ul><li>Brain </li></ul></ul><ul><ul><li>Liver </li></ul></ul><ul><ul><ul><li>Removes ammonia intestinal tract </li></ul></ul></ul><ul><ul><ul><ul><li>Bacterial deamination of amino acids </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Glutamine utilization in intestinal cells </li></ul></ul></ul></ul>
  18. 19. Clinical Case Study <ul><li>Male infant, 2.9 kg at birth, healthy </li></ul><ul><li>Day 3 - seizures </li></ul><ul><li>Mother with history of aversion to meat </li></ul><ul><ul><li>vomiting and lethargy </li></ul></ul><ul><li>mild alkalosis (pH=7.5, normal 7.35-7.45) </li></ul><ul><li>plasma NH 4 + = 240 uM (25-40 normal) </li></ul>
  19. 20. Clinical Case Study <ul><li>Plasma AA </li></ul><ul><ul><li>gln = 2400 uM (350-650) </li></ul></ul><ul><ul><li>ala = 750 uM (8-25) </li></ul></ul><ul><ul><li>arg = 5 uM (30-125) </li></ul></ul><ul><ul><li>cit = undetectable </li></ul></ul><ul><li>Urinary orotic acid = 285 ug/mg creatinine (0.3-10) </li></ul>
  20. 21. Clinical Case Study <ul><li>Treatment </li></ul><ul><ul><li>Oral therapy essential amino acids </li></ul></ul><ul><ul><li>arginine </li></ul></ul><ul><ul><li>sodium benzoate </li></ul></ul><ul><li>@7 days clinically well </li></ul><ul><ul><li>normal NH 4 + </li></ul></ul>
  21. 22. Overview of Amino Acid Nitrogen Metabolism: moving amino acid nitrogen to the liver safely <ul><li>Catabolism of amino acids results in: </li></ul><ul><ul><li>Carbon skeleton </li></ul></ul><ul><ul><ul><li>Source for energy </li></ul></ul></ul><ul><ul><ul><li>Gluconeogenesis or fat synthesis in liver </li></ul></ul></ul><ul><ul><li>Nitrogen </li></ul></ul><ul><ul><ul><li>Excreted as urea, synthesized in liver </li></ul></ul></ul><ul><li>Muscle </li></ul><ul><ul><li>Move most N onto ALA and GLN for transport to liver </li></ul></ul><ul><li>Liver </li></ul><ul><ul><li>Move N from ALA and GLN onto ASP and NH 3 for urea synthesis </li></ul></ul>
  22. 23. Detoxification of Ammonia by the Liver: the Urea Cycle <ul><li>Amino acid N flowing to liver as: </li></ul><ul><ul><li>Alanine & glutamine </li></ul></ul><ul><ul><li>Other amino acids </li></ul></ul><ul><ul><li>Ammonia (from portal blood) </li></ul></ul><ul><li>Urea </li></ul><ul><ul><li>chief N-excretory compound </li></ul></ul>
  23. 24. Detoxification of Ammonia by the Liver: the Urea Cycle <ul><ul><li>Liver </li></ul></ul><ul><ul><li>Contains all enzyme of urea cycle </li></ul></ul><ul><ul><li>Site of urea synthesis </li></ul></ul>
  24. 25. Flow of Nitrogen from Amino Acids to Urea in Liver <ul><li>Amino acid flow from muscle to liver </li></ul><ul><ul><li>Alanine & glutamine </li></ul></ul><ul><li>Liver </li></ul><ul><ul><li>Transfers N to GLU </li></ul></ul><ul><ul><ul><li>GLN’ase </li></ul></ul></ul><ul><ul><ul><li>Transaminases </li></ul></ul></ul><ul><ul><li>Transfers GLU-N to: </li></ul></ul><ul><ul><ul><li>ASP </li></ul></ul></ul><ul><ul><ul><ul><li>AST </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Transamination route </li></ul></ul></ul></ul></ul><ul><ul><ul><li>NH3 </li></ul></ul></ul><ul><ul><ul><ul><li>GDH </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Trans-deamination route </li></ul></ul></ul></ul></ul><ul><ul><li>Transfers N to urea </li></ul></ul>
  25. 26. Ammonia detoxification by the liver <ul><li>Liver very effective at eliminating ammonia from blood </li></ul><ul><ul><li>Portal blood ammonia = 300uM </li></ul></ul><ul><ul><li>Systemic blood ammonia = 20uM </li></ul></ul><ul><li>Periportal hepatocytes </li></ul><ul><ul><li>Urea synthesis </li></ul></ul><ul><li>Perivenous hepatocytes </li></ul><ul><ul><li>Glutamine synthesis </li></ul></ul><ul><ul><ul><li>Very low Km for ammonia </li></ul></ul></ul>
  26. 27. Clinical Case Study <ul><li>Male infant, 2.9 kg at birth, healthy </li></ul><ul><li>Day 3 - seizures </li></ul><ul><li>Mother with history of aversion to meat </li></ul><ul><ul><li>vomiting and lethargy </li></ul></ul><ul><li>plasma NH 4 + = 240 uM (25-40 normal) </li></ul><ul><ul><li>hyperammonemia </li></ul></ul><ul><ul><li>mild alkalosis (pH=7.5, normal 7.35-7.45) </li></ul></ul>
  27. 28. Clinical Case Study <ul><li>Plasma AA </li></ul><ul><ul><li>gln = 2400 uM (350-650) </li></ul></ul><ul><ul><li>ala = 750 uM (8-25) </li></ul></ul><ul><ul><li>arg = 5 uM (30-125) </li></ul></ul><ul><ul><li>cit = undetectable </li></ul></ul><ul><li>Urinary orotic acid = 285 ug/mg creatinine (0.3-10) </li></ul>
  28. 29. Resolution of Clinical Case <ul><li>Diagnosis of neonatal hyperammonemia </li></ul><ul><ul><li>symptoms </li></ul></ul><ul><ul><li>blood ammonium concentration </li></ul></ul><ul><li>Defect in urea cycle </li></ul><ul><ul><li>elevated glutamine and alanine </li></ul></ul><ul><ul><li>low or absent arginine and citrulline </li></ul></ul>
  29. 30. Resolution of Clinical Case <ul><li>Genetic deficiency of ornithine transcarbamoylase </li></ul><ul><ul><li>urinary orotic acid </li></ul></ul><ul><ul><ul><li>CP spills into cytosol where enters pyrimidine biosynthetic pathway, orotic acid an intermediate in the pathway </li></ul></ul></ul>
  30. 31. Detoxification of Ammonia by the Liver: the Urea Cycle
  31. 32. Clinical Case Study <ul><li>Treatment </li></ul><ul><ul><li>Oral therapy essential amino acids </li></ul></ul><ul><ul><li>arginine </li></ul></ul><ul><ul><li>sodium benzoate </li></ul></ul><ul><li>@7 days clinically well </li></ul><ul><ul><li>normal NH 4 + </li></ul></ul>
  32. 33. Resolution of Clinical Case: Treatment <ul><ul><li>Essential Amino Acids </li></ul></ul><ul><ul><li>Arginine </li></ul></ul><ul><ul><ul><li>w/o urea cycle, becomes essential </li></ul></ul></ul><ul><ul><li>Benzoic acid </li></ul></ul><ul><ul><ul><li>conjugates with glycine and excreted in urine as hippuric acid </li></ul></ul></ul><ul><ul><ul><li>glycine in equilibrium with ammonia </li></ul></ul></ul><ul><ul><ul><li>removal results in reducing ammonia levels </li></ul></ul></ul>
  33. 34. Resolution of Clinical Case: Genetics <ul><li>Gene for OTC found on X-chromosome </li></ul><ul><li>Women are carriers </li></ul><ul><ul><li>usually asymptomatic </li></ul></ul><ul><ul><li>may experience migraines, vomiting, lethargy when eating high protein meals (meat) </li></ul></ul>

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