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After studying this chapter, you should be able to:

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  • Describe protein turnover, indicate the mean rate of protein turnover in healthy individuals, and provide examples of human proteins that are degraded at rates greater than the mean rate.
  • Describe the events in protein turnover by both ATP-dependent and ATP-independent pathways, and the roles in protein degradation of ubiquitin, cell surface receptors, circulating asialoglycoproteins, and lysosomes.
  • Indicate how the ultimate end products of nitrogen catabolism in mammals differ from those in birds and in fish.
  • Illustrate the central roles of transaminases (aminotransferases), of glutamate dehydrogenase, and of glutaminase in human nitrogen metabolism.
  • Use structural formulas to represent the reactions that convert NH3, CO2, and the amide nitrogen of aspartate into urea.
  • Indicate the subcellular locations of the enzymes that catalyze urea biosynthesis, and the roles of allosteric regulation and of acetylglutamate in the regulation of this process.
  • Explain why metabolic defects in different enzymes of urea biosynthesis, although distinct at the molecular level, present similar clinical signs and symptoms.
  • Describe both the classical approaches and the role of tandem mass spectrometry in screening neonates for inherited metabolic diseases.

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This chapter describes how the nitrogen of amino acids is converted to urea and the rare metabolic disorders that accompany defects in urea biosynthesis. In normal adults, nitrogen intake matches nitrogen excreted. Positive nitrogen balance, an excess of ingested over excreted nitrogen, accompanies growth and pregnancy. Negative nitrogen balance, where output exceeds intake, may follow surgery, advanced cancer, and the nutritional disorders kwashiorkor, and marasmus. Ammonia, which is highly toxic, arises in humans primarily from the α-amino nitrogen of amino acids. Tissues therefore convert ammonia to the amide nitrogen of the nontoxic amino acid glutamine. Subsequent deamination of glutamine in the liver releases ammonia, which is then converted to urea, which is not toxic. If liver function is compromised, as in cirrhosis or hepatitis, elevated blood ammonia levels generate clinical signs and symptoms. Each enzyme of the urea cycle provides examples of metabolic defects and their physiologic consequences, and the cycle as a whole serves as a molecular model for the study of human metabolic defects.

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The continuous degradation and synthesis (turnover) of cellular proteins occur in all forms of life. Each day, humans turn over 1–2% of their total body protein, principally muscle protein. High rates of protein degradation occur in tissues that are undergoing structural rearrangement, for example, uterine tissue during pregnancy, skeletal muscle in starvation, and tadpole tail tissue during metamorphosis. Approximately 75% of the amino acids liberated by protein degradation are reutilized. Excess free amino acids are, however, not stored. Those not immediately incorporated into new protein are rapidly degraded. The major portion of the carbon skeletons of the amino acids is converted to amphibolic intermediates, while in humans the amino nitrogen is converted to urea and excreted in the urine.

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The relative susceptibility of a protein to degradation is ...

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