chapter 18 amino acid oxidation production of urea n.
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CHAPTER 18 Amino Acid Oxidation Production of Urea

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CHAPTER 18 Amino Acid Oxidation Production of Urea

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  1. CHAPTER 18Amino Acid OxidationProduction of Urea • How proteins are digested in animals • How amino acids are degraded in animals • How urea is made in made and excreted Key topics:

  2. Oxidation of Amino Acids is a Significant Energy-Yielding Pathway in Carnivores • Not all organisms use amino acids as the source of energy • About 90% of energy needs of carnivores can be met by amino acids immediately after a meal • Only a small fraction of energy needs of herbivores are met by amino acids • Microorganisms scavenge amino acids from their environment for fuel

  3. Metabolic Circumstances of Amino Acid Oxidation Amino acids undergo oxidative catabolism under three circumstances: • Protein amino-acid residues from normal turnover are recycled to generate energy and molecular components • Dietary amino acids that exceed body’s protein synthesis needs are degraded • Proteins in the body are broken down to supply amino acids for catabolism when carbohydrates are in short supply (starvation, diabetes mellitus),

  4. Dietary Proteins are Enzymatically Hydrolyzed • Pepsin cuts protein into peptides in the stomach • Trypsin and chymotrypsin cut proteins and larger peptides into smaller peptides in the small intestine • Aminopeptidase and carboxypeptidases A and B degrade peptides into amino acids in the small intestine

  5. (a) gastrin -> secretion of HCl by parietal cells and pepsin by chief cells (b) exocrine cells synthesize zymogens zymogen granules fuse with plasma membrane zymogens released into the lumen of the collecting duct collecting ducts -> pancreatic duct -> small intestine. (c) Amino acids -> villi -> capillaries Enzymatic Degradation of Dietary Proteins

  6. Overview of Amino Acid Catabolism

  7. The Amino Group is Removed From All Amino Acids First

  8. Fates of Nitrogen in Organisms • Plants conserve almost all the nitrogen • Many aquatic vertebrates release ammonia to their environment • Passive diffusion from epithelial cells • Active transport via gills • Many terrestrial vertebrates and sharks excrete nitrogen in the form of urea • Urea is far less toxic that ammonia • Urea has very high solubility • Some animals, such as birds and reptiles excrete nitrogen as uric acid • Uric acid is rather insoluble • Excretion as paste allows to conserve water • Humans and great apes excrete both urea (from amino acids) and uric acid (from purines)

  9. Excretory Forms of Nitrogen

  10. Enzymatic Transamination • Typically, -ketoglutarate accepts amino groups • L-Glutamine acts as a temporary storage of nitrogen • L-Glutamine can donate the amino group when needed for amino acid biosynthesis • All aminotransferases rely on the pyridoxal phosphate cofactor

  11. Structure of Pyridoxal Phosphate and Pyridoxamine Phosphate • Intermediate, enzyme-bound carrier of amino groups • Aldehyde form can react reversibly with amino groups • Aminated form can react reversibly with carbonyl groups

  12. Pyridoxal Phosphate is Covalently Linked to the Enzyme at Rest • The linkage is made via an nucleophilic attack of the amino group an active-site lysine side chain • After dehydration, a Schiff base linkage is formed • The covalent complex is called internal aldimine because the Schiff base connects PLP to the enzyme

  13. Internal Aldimine in Aspartate Aminotransferase (Lys258-purple)

  14. Chemistry of the Amino Group Removal by the Internal Aldimine • The external aldimine of PLP is a good electron sink, allowing removal of -hydrogen

  15. PLP Also Catalyzes Racemization of Amino Acids • The external aldimine of PLP is a good electron sink, allowing removal of -hydrogen

  16. PLP Also Catalyzes Decarboxylation of Amino Acids • The external aldimine of PLP is a good electron sink, allowing removal of -carboxylate

  17. Ammonia in Transported in the Bloodstream Safely as Glutamate • Un-needed glutamine is processed in intestines, kidneys and liver

  18. Glutamate can Donate Ammonia to Pyruvate to Make Alanine • Vigorously working muscles operate nearly anaerobically and rely on glycolysis for energy • Glycolysis yields pyruvate that muscles cannot metabolize aerobically; if not eliminated lactic acid will build up • This pyruvate can be converted to alanine for transport into liver

  19. Excess Glutamate is Metabolized in the Mitochondria of Hepatocytes

  20. The Glutamate Dehydrogenase Reaction • Two-electron oxidation of glutamate followed by hydrolysis • Net process is oxidative deamination of glutamate • Occurs in mitochondrial matrix in mammals • Can use either NAD+ or NADP+ as electron acceptor

  21. Ammonia is Re-captured via Synthesis of Carbamoyl Phosphate • This is the first nitrogen-acquiring reaction

  22. Nitrogen from Carbamoyl Phosphate Enters the Urea Cycle

  23. The Reactions in the Urea Cycle • 1 ornithine + carbamoyl phosphate => citrulline • (entry of the first amino group). • citrulline passes into the cytosol. • 2a citrulline + ATP => citrullyl-AMP + PPi • 2b citrullyl-AMP + Aspartate => argininosuccinate + AMP • (entry of the second amino group). • 3 argininosuccinate => arginine + fumarate • fumarate enters the citric acid cycle. • 4 arginine => urea + ornithine • Ornithine passes to the mitochondria to continue the cycle

  24. Urea Cycle N-2 from Aspartate

  25. Entry of Aspartate into the Urea Cycle • This is the second nitrogen-acquiring reaction

  26. Aspartate –Arginosuccinate Shunt Links Urea Cycle and Citric Acid Cycle

  27. Not All Amino Acids can be Synthesized in Humans • These amino acids must be obtained as dietary protein • Consumption of a variety of foods (including vegetarian only diets) well supplies all the essential amino acids

  28. Fate of Individual Amino Acids • Seven to acetyl-CoA • Leu, Ile, Thr, Lys, Phe, Tyr, Trp • Six to pyruvate • Ala, Cys, Gly, Ser, Thr, Trp • Five to -ketoglutarate • Arg, Glu, Gln, His, Pro • Four to succinyl-CoA • Ile, Met, Thr, Val • Two to fumarate • Phe, Tyr • Two to oxaloacetate • Asp, Asn

  29. Summary of Amino Acid Catabolism

  30. Biotin – single C transfers as CO2 Eg. Pyruvate Carboxylase

  31. Tetrahydrofolate Single Carbon Transfers – intermediate oxidation state – methylene, formyl, …

  32. S-Adenosyl Methionine Methyl Transfers

  33. 6 Aminon Acids -> Pyruvate Ala, Gly, Ser, Cys,Trp,Thr.

  34. A third Mechanism for Glycine Degradation D-Amino Acids prominent in bacterial peptidoglycan Calcium Oxalate – 75% of Kidney Stones

  35. 7 AAs -> Acetyl CoA [W,K,F,Y, L]

  36. 7 AAs -> Acetyl CoA [ I , L]; T not shown

  37. W, indole Ring Recycling

  38. Metabolic Diseases – Defects of Aromatic AA degradation

  39. R, H, P, E,Q -> α- ketoglutarate

  40. I, M, T, V-> Succinyl-CoA

  41. Branched-chain amino acids: valine, isoleucine, and leucine.

  42. Asp and Asn to oxaloacetate.

  43. Summary of Amino Acid Catabolism

  44. Chapter 18: Summary In this chapter, we learned that: • Amino acids from protein are an important energy source in carnivorous animals • Catabolism of amino acids involves transfer of the amino group via PLP-dependent aminotransferase to a donor such as -ketoglutarate to yield L-glutamine • L-glutamine can be used to synthesize new amino acids, or it can dispose of excess nitrogen as ammonia • In most mammals, toxic ammonia is quickly recaptured into carbamoyl phosphate and passed into the urea cycle