Figure 29–13 illustrates the intermediates and enzymes that participate in the catabolism of tyrosine to amphibolic intermediates. Following transamination of tyrosine to p-hydroxyphenylpyruvate, successive reactions form maleylacetoacetate, fumarylacetoacetate, fumarate, acetoacetate, and ultimately acetyl-CoA and acetate.
Several metabolic disorders are associated with the tyrosine catabolic pathway. The probable metabolic defect in type I tyrosinemia (tyrosinosis) is at fumarylacetoacetate hydrolase, EC 220.127.116.11 (reaction 4, Figure 29–13). Therapy employs a diet low in tyrosine and phenylalanine. Untreated acute and chronic tyrosinosis leads to death from liver failure. Alternate metabolites of tyrosine are also excreted in type II tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine aminotransferase (reaction 1, Figure 29–13), and in neonatal tyrosinemia, due to lowered activity of p-hydroxyphenylpyruvate hydroxylase, EC 18.104.22.168 (reaction 2, Figure 29–13). Therapy employs a diet low in protein.
The metabolic defect in alkaptonuria is a defective homogentisate oxidase (EC 22.214.171.124), the enzyme that catalyzes reaction 3 of Figure 29–13. The urine darkens on exposure to air due to oxidation of excreted homogentisate. Late in the disease, there is arthritis and connective tissue pigmentation (ochronosis) due to oxidation of homogentisate to benzoquinone acetate, which polymerizes and binds to connective tissue. First described in the sixteenth century based on the observation that the urine darkened on exposure to air, alkaptonuria provided the basis for Sir Archibald Garrod’s early twentieth century classic ideas concerning heritable metabolic disorders. Based on the presence of ochronosis and on chemical evidence, the earliest known case of alkaptonuria is, however, its 1977 detection in an Egyptian mummy dating from 1500 b.c.
Phenylalanine is first converted to tyrosine (see Figure 27–12). Subsequent reactions are those of tyrosine (Figure 29–13). Hyperphenylalaninemias arise from defects in phenylalanine hydroxylase, EC 126.96.36.199 (type I, classic phenylketonuria (PKU), frequency 1 in 10,000 births), in dihydrobiopterin reductase (types II and III), or in dihydrobiopterin biosynthesis (types IV and V) (see Figure 27–12). Alternative catabolites are excreted (Figure 29–14). A diet low in phenylalanine can prevent the mental retardation of PKU.
Alternative pathways of phenylalanine catabolism in phenylketonuria. The reactions also occur in normal liver tissue but are of minor significance.
DNA probes facilitate prenatal diagnosis of defects in phenylalanine hydroxylase or dihydrobiopterin reductase. Elevated blood phenylalanine may not be detectable until 3 to 4 days postpartum. False-positives in premature infants may reflect delayed maturation of enzymes of phenylalanine catabolism. An older and less reliable screening test employs FeCl3 to detect urinary phenylpyruvate. FeCl3 screening for PKU of the urine of newborn infants is compulsory in many countries, but in the United States has been largely supplanted by tandem mass spectrometry.
The first six reactions of l-lysine catabolism in human liver form crotonyl-CoA, which is then degraded to acetyl-CoA by the reactions of fatty acid catabolism (see Chapter 22). In what follows, circled numerals refer to the corresponding numbered reactions of Figure 29–15. Reactions 1 and 2 convert the Schiff base formed between α-ketoglutarate and the ε-amino group of lysine to l-α-aminoadipate-δ-semialdehde. Reactions 1 and 2 both are catalyzed by a single bifunctional enzyme, aminoadipate semialdehde synthase (EC 188.8.131.52) whose N-terminal and C-terminal domains contain lysine-α-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively. Reduction of l-α-aminoadipate-δ-semialdehde to l-α-aminoadipate (reaction 3) is followed by transamination to α-ketoadipate (reaction 4). Conversion to the thioester glutaryl- CoA (reaction 5) is followed by the decarboxylation of glutaryl- CoA to crotonyl-CoA (reaction 6). Subsequent reactions are those of fatty acid catabolism.
Reactions and intermediates in the catabolism of lysine.
Hyperlysinemia can result from a metabolic defect in either the first or second activity of the bifunctional enzyme aminoadipate semialdehde synthase, but this is accompanied by elevated levels of blood saccharopine only if the defect involves the second activity. A metabolic defect at reaction 6 results in an inherited metabolic disease that is associated with striatal and cortical degeneration, and is characterized by elevated concentrations of glutarate and its metabolites glutaconate and 3-hydroxyglutarate. The challenge in management of these metabolic defects is to restrict dietary intake of l-lysine without producing malnutrition.
Tryptophan is degraded to amphibolic intermediates via the kynurenine-anthranilate pathway (Figure 29–16). Tryptophan 2,3-dioxygenase, EC 184.108.40.206 (tryptophan pyrrolase) opens the indole ring, incorporates molecular oxygen, and forms N-formylkynurenine. Tryptophan oxygenase, an iron porphyrin metalloprotein that is inducible in liver by adrenal corticosteroids and by tryptophan, is feedback inhibited by nicotinic acid derivatives, including NADPH. Hydrolytic removal of the formyl group of N-formylkynurenine, catalyzed by kynurenine formylase (EC 220.127.116.11), produces kynurenine. Since kynureninase (EC 18.104.22.168) requires pyridoxal phosphate, excretion of xanthurenate (Figure 29–17) in response to a tryptophan load is diagnostic of vitamin B6 deficiency. Hartnup disease reflects impaired intestinal and renal transport of tryptophan and other neutral amino acids. Indole derivatives of unabsorbed tryptophan formed by intestinal bacteria are excreted. The defect limits tryptophan availability for niacin biosynthesis and accounts for the pellagra-like signs and symptoms.
Reactions and intermediates in the catabolism of tryptophan. (PLP, pyridoxal phosphate.)
Formation of xanthurenate in vitamin B6 deficiency. Conversion of the tryptophan metabolite 3-hydroxykynurenine to 3-hydroxyanthranilate is impaired (see Figure 29–16). A large portion is therefore converted to xanthurenate.
Methionine reacts with ATP forming S-adenosylmethionine, “active methionine” (Figure 29–18). Subsequent reactions form propionyl-CoA (Figure 29–19), which three subsequent reactions convert to succinyl-CoA (see Figure 19–2).
Formation of S-adenosylmethionine. ~ CH3 represents the high group transfer potential of “active methionine.”
Conversion of methionine to propionyl-CoA.