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Metabolism of Amino Acid (Carbon Skeletons) Part 2

TUMS. Metabolism of Amino Acid (Carbon Skeletons) Part 2. Dr. Azin Nowrouzi Tehran University of Medical Sciences. Fate of the C-Skeleton of Amino Acids. 2. Outline of catabolism of 20 amino acids. 4. 5. Degradation of Carbon Skeletons. 6.

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Metabolism of Amino Acid (Carbon Skeletons) Part 2

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  1. TUMS Metabolism of Amino Acid (Carbon Skeletons) Part 2 Dr. Azin Nowrouzi Tehran University of Medical Sciences

  2. Fate of the C-Skeleton of Amino Acids 2

  3. Outline of catabolism of 20 amino acids 4

  4. 5

  5. Degradation of Carbon Skeletons 6 • Seven products result from the catabolism of amino acid carbon skeletons: • oxaloacetate, α-ketoglutarate, pyruvate, fumarate, acetyl coA, acetoacetyl coA, succinyl coA • Glycogenic • Their catabolism produces pyruvate or one of the intermediates of the Crebs cycle. • These are substrates for gluconeogenesis • So they can produce glycogen in liver and muscle. • Lipogenic (or ketogenic) • Their catabolism produces acetoacetate or its precursors acetyl coA or acetoacetyl coA

  6. Amino Acids that produce Oxaloacetate

  7. Amino Acids that produce α-ketoglutarate

  8. Amino Acids that produce Pyruvate

  9. Amino Acids that produce Fumarate

  10. Phenylketonuria (PKU) Disease • Deficiency of Phe hydroxylase • Occurs in 1:20,000 live births in U.S. • Seizures, mental retardation, brain damage • Treatment: limit phenylalanine intake • Screening of all newborns mandated in all states 11

  11. Amino Acids that produce Acetyl CoA or Acetoacetyl CoA

  12. Amino Acids that produce Succinyl CoA

  13. Catabolism of Branched Chain Amino Acids

  14. Transfer of nitrogen components from tissues to the liver for urea synthesis

  15. Fed state 16

  16. Fasting (starvation) (i) For the first 7 days, maintain blood glucose (brain use 65% of glucose  400 - 600 Cal) (ii) > 7 days: Protein proteolysis decreases (protect essential proteins) therefore use over a prolonged period compromises organism. (iii) → Switch to Ketone bodies 17

  17. 18

  18. AA are released from muscle during the post- absorptive state (O/N fast). Of the AA released by muscle Ala= 30% & Gln= 25% (total> 50%) But output (Ala+Gln) > abundance in muscle proteins which contain 7-10% Ala & 6% Gln Where does this Ala & Gln come from? 19

  19. Sources of Alanine (from Muscle) (i)Muscle: Protein → Ala + aa aa→ NH4+ + α keto acids α keto acids → Ala (“simplest” aa). Therefore total Ala released > Ala derived from proteins (ii) Liver: Ala →NH4+ + α keto acids NH4+→ urea (iii) As well Glucose → Pyruvate (no N) → Ala (with N) Therefore Ala serves as a vehicle for transport of NH4+ from muscle to liver (NH4+ is generated through breakdown of aa  →energy). (iv) Because free NH4+ is very toxic even at low levels therefore Pyruvate + NH4+ →Ala (non-toxic) (v) In liver: NH4+ → urea for excretion 20

  20. Specialized Amino Acid Roles 1. Certain NEAA continue being synthesized even when adequate levels are supplied in diet because of a specialized role 2. ARG → urea synthesis ASP → urea synthesis GLU → conduit for disposal of N 3. ALA & GLN → key role in exchange between tissues (liver & skeletal muscle) 4. Liver: major site gluconeogenesis (AA → Glucose) major site urea synthesis (kidneys to a lesser extent) 5. Skeletal Muscle: 60% total body protein, 50% total body AA pool and is the major source to provide AA carbons → hepatic gluconeogenesis 21

  21. Amino Acid Degradation 22 • Removal of alpha-amino groups • Nitrogen excretion • Fate of carbon skeletons

  22. Removal of alpha-amino groups 23 • Mechanisms of –NH2 removal • Transamination • Oxidative deamination • Amino acid oxidases • Threonine or Serine dehydratase

  23. A. Transamination Removal of Nitrogen by aminotransferase 24

  24. B. Oxidative Deamination 25

  25. L- and D- Amino Acid Oxidases • They are present in liver and kidneys. • They have low activity • Their physiologic value is not clear. Amino Acid + H2O α-ketoacid + NH3

  26. D. Amino acid Dehydratase Threonine Urea 27 Serine and Threonine can be Directly Deaminated

  27. Fate of Nitrogen in Different Organisms • Other excretion products • creatinine • uric acid 28

  28. Disposal of amino group 29 • Urea cycle (Krebs-Henseleit cycle) • Provides 25-30 g of urea daily for urine formation in the kidneys • Carbamoyl Phosphate Synthetase • Ornitine Carbamoyl Transferase • Argininosuccinate Synthetase • Argininosuccinate Lyase • Arginase • Excretion of free ammonia • Glutamine synthetase • Glutaminase

  29. Ammonium Ion is Converted into Urea Urea cycle 31

  30. The Urea Cycle is Linked to the Citric Acid Cycle NH4+ 32

  31. Amino Acid Metabolism 33

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