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INTRODUCTION

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OBJECTIVES

After studying this chapter, you should be able to:

  • Name the principal catabolites of the carbon skeletons of the protein 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 protein 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 Δ1-pyrroline-5-carboxylate 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.

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BIOMEDICAL IMPORTANCE

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Chapter 28 described the removal by transamination and the metabolic fate of the nitrogen atoms of most of the protein l-α-amino acids. This chapter addresses the metabolic fates of the resulting hydrocarbon skeletons of each of the protein amino acids. The topics include the enzymes, the intermediates formed during the catabolism of the carbon skeletons to amphibolic intermediates, and several associated metabolic diseases or “inborn errors of metabolism.” Most disorders of amino acid catabolism are rare, but 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 up to 40 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.

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Mutations either of a gene or of associated regulatory regions of DNA can result either in the failure to synthesize the encoded enzyme or in synthesis of a partially or completely nonfunctional enzyme. While some mutations do not adversely affect enzyme activity, mutations that compromise an enzyme’s three-dimensional structure, or that disrupt catalytic or regulatory sites of an enzyme, can have severe metabolic consequences. Low catalytic efficiency of a mutant enzyme can result from impaired positioning of residues ...

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