Chapter 29

After studying this chapter, you should be able to:

• Name the principal catabolites of the carbon skeletons of the common amino acids and the major metabolic fates of these catabolites.
• Write an equation for an aminotransferase (transaminase) reaction and illustrate the role played by the coenzyme.
• Outline the metabolic pathways for each of the common amino acids, and identify reactions associated with clinically significant metabolic disorders.
• Provide examples of aminoacidurias that arise from defects in glomerular tubular reabsorption, and the consequences of impaired intestinal absorption of tryptophan.
• Explain why metabolic defects in different enzymes of the catabolism of a specific amino acid can be associated with similar clinical signs and symptoms.
• Describe the implications of a metabolic defect in glutamate-γ-semialdehyde dehydrogenase for the catabolism of proline and of 4-hydroxyproline.
• Explain how the α-amino nitrogen of proline and of lysine is removed by processes other than transamination.
• Draw analogies between the reactions that participate in the catabolism of fatty acids and of the branched-chain amino acids.
• Identify the specific metabolic defects in hypervalinemia, maple syrup urine disease, intermittent branched-chain ketonuria, isovaleric acidemia, and methylmalonic aciduria.

The prior chapter described the removal and metabolic fate of the nitrogen atoms of the common L-α-amino acids. This chapter will address the metabolic fates of the resulting hydrocarbon skeletons of these amino acids. Discussed are the enzymes and intermediates formed during the conversion of the carbon skeletons to amphibolic intermediates, and several metabolic diseases or “inborn errors of metabolism” associated with these processes. While most disorders of amino acid catabolism are rare, if left untreated they can result in irreversible brain damage and early mortality. Prenatal or early postnatal detection of metabolic disorders and timely initiation of treatment thus are essential. The ability to detect the activities of enzymes in cultured amniotic fluid cells facilitates prenatal diagnosis by amniocentesis. All states now conduct screening tests of newborns for as many as 30 metabolic diseases. These tests include, but are not limited to, disorders associated with defects in the catabolism of amino acids. The most reliable screening tests use tandem mass spectrometry to detect, in a few drops of neonate blood, catabolites suggestive of a given metabolic defect. The metabolites detected pinpoint the metabolic defect as the lowered or absent activity of a given enzyme. Treatment consists primarily of feeding diets low in the amino acid whose catabolism is impaired.

Mutations in the exons or in the regulatory regions of a gene that encodes an enzyme of amino acid metabolism can result in the failure to synthesize that enzyme or in the synthesis of a partially or completely nonfunctional enzyme. Mutations may have no significant effect of the activity of the encoded enzyme. By contrast, mutations that compromise the overall three-dimensional structure or the structure of catalytic or regulatory sites may be associated with adverse metabolic consequences. Low catalytic efficiency of a mutant enzyme can result from impaired positioning of residues involved in ...

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