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Section 8. Amino Acid Metabolism

Section 8. Amino Acid Metabolism. Urea cycle. 11/18/05. Substrates for the Urea Cycle. Above, amino groups are transferred to glutamate, from which ammonium is produced, and then used to make carbamoyl phosphate . Below, amino groups are transferred to produce aspartate . 1. Urea Cycle.

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Section 8. Amino Acid Metabolism

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  1. Section 8. Amino Acid Metabolism Urea cycle 11/18/05

  2. Substrates for the Urea Cycle • Above, amino groups are transferred to glutamate, from which ammonium is produced, and then used to make carbamoyl phosphate. • Below, amino groups are transferred to produce aspartate. 1

  3. Urea Cycle • Aspartate and carbamoyl phosphate each deliver an amino group to the cycle. • Notice that the carbamoyl phosphate production and condensation occur in the mitochondrial matrix. Fig. 23.16 2

  4. NH4+ from Oxidative Deamination of Glutamate • Hexameric glutamate dehydrogenase is is controlled allosterically. • High energy levels inhibit (ATP and GTP). • Low energy levels activate (ADP and GDP). • NADP+ can replace NAD+. • NH4+ , which is toxic to humans, is produced in the mitochondria and used to make carbamoyl phosphate. 3

  5. Carbamoyl Phosphate Synthesis • Carbamoyl phosphate synthetase is in mitochondrial matrix. • NH4+ is source of NH3. • The hydrolysis of two ATP make this reaction essentially irreversible. • N-acetyl glutamate is an allosteric activator. (see S08L05) (p. 645) 4

  6. 2 ~ P used 1. ARGININOSUCCINATE SYNTHASE 2. ARGININOSUCCINASE 3. ARGINASE 4. ORNITHINE TRANSCARBAMOYLASE 5

  7. Connection to Krebs Cycle • Fumarate is oxidized to oxaloacetate by Krebs cycle enzymes, producing NADH. • Oxaloacetate accepts an amino group instead of being condensed with acetyl CoA. 6

  8. Amino Acids to Urea *Glutamate Dehydrogenase is the control site: ADP (+), GDP (+), ATP (-), GTP (-) and NADH (-). Control at other sites by glucagon (+), cortisol (+), insulin (-), growth hormone (-). 7

  9. Summary of Reactions and Energetics - 1 H20 + aa + NAD+-keto acid + NH4+ + NADH + H+ and H20 + fumarate + aa + NAD+ aspartate + -keto acid + NADH + H+ then aspartate + NH4+ + HCO3- + 3 ATP  urea + fumarate + 2 H20 + 2 ADP + AMP + 4 Pi + H+ Four high energy phosphate bond equivalents are used for these reactions (- 4 ~P). Two NADH are produced. 8

  10. Summary of Reactions and Energetics - 2 Now consider NADH oxidation: 2 H+ + 2 NADH + O22 NAD+ + 2 H20 (+5 ~P) The net reaction is then 2 aa + HCO3- + O2 2 -keto acid + urea + H+ + 2 H20 (+1~P) 9

  11. Hyperammonemia • Normal blood [NH4+] is 10-40 mM. • Deficiencies of carbamoyl phosphate synthetase or of any enzyme in the urea cycle cause high [NH4+]. • Affects CNS and can lead to irreversible brain damage. • Treatment strategies depend on which enzyme is deficient. 10

  12. Low dietary protein reduces need for urea cycle. High dietary arginine provides a path for carbamoyl phosphate and aspartate nitrogens to produce argininosuccinate, which is excreted. Argininosuccinase Deficiency 11

  13. Carbamoyl Phosphate Synthetase Deficiency • Hippurate and phenylacetylglutamine are excreted. • Amino groups to glycine and glutamine by transamination. Fig. 23.20 12

  14. Ketogenic and Glucogenic Amino Acids • After removal of the amino group, the keto acids are used to make Krebs cycle intermediates, pyruvate, acetyl CoA and acetoacetyl CoA. Fig. 23.21 13

  15. Nitrogen for Oral Bacteria • Urea is a major source of nitrogen for oral bacteria. • It diffuses through most membranes and is in saliva. • Bacterial urease produces NH4+. • Glutamate dehydrogenase incorporates NH4+ into -keto acids to obtainamino acids for bacterial growth. 14

  16. Nitrogen for Bacterial Amino Acid Synthesis • When [NH4+] is limiting, it does not bind glutamate dehydrogenase, and the lower two reactions are used. 15

  17. Engineered Oral Bacteria to Fight Caries? • Streptococcus Salivarius urease activity affects oral microbial ecology. • It produces NH3, which in addition to promoting growth, neutralizes acids produces by other bacteria. • S. Salivarius urease gene was introduced into Streptococcus mutans GS5. It was expressed and during glucose metabolism reduced pH decrease and duration. • (Clancy & Burne,1997 FEMS Microbiol Lett 151:205) 16

  18. Web links Nitrogen Fixation. A summary of the topic. Nitrogen Cycle. The biological big picture. Amino Acid Metabolism. Reviews reactions. Next topic: Porphyrins, heme, bile pigments

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