Glucogenic amino acids, including glutamine, glutamate, proline, arginine, histidine, alanine, serine, glycine, cysteine, methionine, valine, threonine, aspartate, and asparagine, can be catabolized to yield pyruvate or an intermediate of the tricarboxylic acid cycle. This catabolism enables the liver and kidneys to produce glucose. On the other hand, ketogenic amino acids, such as leucine and lysine, are catabolized to yield acetoacetate or its precursors, acetyl coenzyme A (CoA) or acetoacetyl CoA. Interestingly, tyrosine, phenylalanine, tryptophan, and isoleucine have the ability to be both ketogenic and glucogenic. Nonessential amino acids can be synthesized from metabolic intermediates or the carbon skeletons of essential amino acids. Essential amino acids, which include histidine, methionine, threonine, valine, isoleucine, phenylalanine, tryptophan, leucine, and lysine, must be obtained from the diet. In individuals with phenylketonuria (PKU), a deficiency of phenylalanine hydroxylase (PAH) leads to a lack of conversion of phenylalanine to tyrosine. This deficiency can also be caused by a deficiency in the enzymes involved in synthesizing or regenerating the coenzyme for PAH, tetrahydrobiopterin, resulting in hyperphenylalaninemia. If left untreated, individuals with PKU may experience severe intellectual disability, developmental delay, microcephaly, seizures, and urine with a musty (mousy) smell. Treatment for PKU involves controlling dietary phenylalanine and supplementing with tyrosine. Maple syrup urine disease (MSUD) occurs due to a partial or complete deficiency in branched-chain a-keto acid dehydrogenase, the enzyme responsible for decarboxylating the branched-chain amino acids leucine, isoleucine, and valine. Symptoms of MSUD include feeding problems, vomiting, ketoacidosis, changes in muscle tone, and urine with a sweet smell. If left untreated, the disease can lead to neurologic problems and death. Treatment for MSUD involves controlling intake of branched-chain amino acids. Other genetic diseases associated with amino acid metabolism include albinism, homocystinuria, methylmalonic acidemia, alkaptonuria, histidinemia, tyrosinemia, and cystathioninuria. Matching the deficient enzyme with the associated clinical sign or laboratory finding in urine, a deficiency in cystathionine β-synthase of methionine degradation results in a rise in homocysteine. A deficiency in homogentisic acid oxidase of tyrosine degradation results in a rise in homogentisic acid, which forms a black pigment that is deposited in connective tissue (ochronosis). A deficiency in tyrosinase leads to decreased formation of melanin from tyrosine in the skin, hair, and eyes. A sweaty feet– like odor is characteristic of isovaleryl coenzyme A dehydrogenase deficiency. Cystine crystals in urine are seen with cystinuria, a defect in intestinal and renal cystine absorption. Increased branched-chain amino acids are seen in maple syrup urine disease, increased methionine is seen in defects in homocysteine metabolism, and increased phenylalanine is seen in phenylketonuria.
Amino acids whose catabolism yields pyruvate or an intermediate of the tricarboxylic acid cycle are termed glucogenic (Fig. 20.24). They can give rise to the net formation of glucose in the liver and kidneys. The solely glucogenic amino acids are glutamine, glutamate, proline, arginine, histidine, alanine, serine, glycine, cysteine, methionine, valine, threonine, aspartate, and asparagine. Amino acids whose catabolism yields either acetoacetate or one of its precursors, acetyl coenzyme A (CoA) or acetoacetyl CoA, are termed ketogenic. Leucine and lysine are solely ketogenic. Tyrosine, phenylalanine, tryptophan, and isoleucine are both ketogenic and glucogenic. Nonessential amino acids can be synthesized from metabolic intermediates or from the carbon skeletons of essential amino acids. Essential amino acids need to be obtained from the diet. They include histidine, methionine, threonine, valine, isoleucine, phenylalanine, tryptophan, leucine, and lysine. Phenylketonuria (PKU) is caused by a deficiency of phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine. Hyperphenylalaninemia may also be caused by deficiencies in the enzymes that synthesize or regenerate the coenzyme for PAH, tetrahydrobiopterin. Untreated individuals with PKU suffer from severe intellectual disability, developmental delay, microcephaly, seizures, and a characteristic musty (mousy) smell of the urine. Treatment involves controlling dietary phenylalanine. Tyrosine becomes an essential dietary component for people with PKU. Maple syrup urine disease (MSUD) is caused by a partial or complete deficiency in branched-chain a-keto acid dehydrogenase, the enzyme that decarboxylates the branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Symptoms include feeding problems, vomiting, ketoacidosis, changes in muscle tone, and a characteristic sweet smell of the urine. If untreated, the disease leads to neurologic problems that result in death. Treatment involves controlling BCAA intake. Other important genetic diseases associated with amino acid metabolism include albinism, homocystinuria, methylmalonic acidemia, alkaptonuria, histidinemia, tyrosinemia, and cystathioninuria.
Choose the ONE best answer.
For Questions 20.1–20.3, match the deficient enzyme with the associated clinical sign or laboratory finding in urine.
0.1. Cystathionine β-synthase 0.2. Homogentisic acid oxidase 0.3. Tyrosinase
Correct answers = F, A, D. A deficiency in cystathionine β-synthase of methionine degradation results in a rise in homocysteine. A deficiency in homogentisic acid oxidase of tyrosine degradation results in a rise in homogentisic acid, which forms a black pigment that is deposited in connective tissue (ochronosis). A deficiency in tyrosinase results in decreased formation of melanin from tyrosine in the skin, hair, and eyes. A sweaty feet– like odor is characteristic of isovaleryl coenzyme A dehydrogenase deficiency. Cystine crystals in urine are seen with cystinuria, a defect in intestinal and renal cystine absorption. Increased branched-chain amino acids are seen in maple syrup urine disease, increased methionine is seen in defects in homocysteine metabolism, and increased phenylalanine is seen in phenylketonuria.