Tyrosine

Figure 1 illustrates the intermediates and enzymes that participate in the catabolism of tyrosine to amphibolic intermediates. Following transamination of tyrosine top-hydroxyphenylpyruvate, successive reactions form homogentisate, maleylacetoacetate, fumarylacetoacetate, fumarate, acetoacetate, and ultimately acetyl-CoA and acetate.

Fig1. Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (α-KG, α-ketoglutarate; Glu, glutamate; PLP, pyridoxal phosphate.) Red bars indicate the probable sites of the inherited metabolic defects in type II tyrosinemia; neonatal tyrosinemia; ➀ alkaptonuria; and ➁ type I tyrosinemia, or tyrosinosis. ➂ alkaptonuria; and ➃ type I tyrosinemia, or tyrosinosis

Several metabolic disorders are associated with the tyrosine catabolic pathway. The probable metabolic defect in type I tyrosinemia (tyrosinosis) is at fumarylacetoacetate hydrolase, EC 3.7.1.12 (reaction 4, see Figure 29–12). 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 amino transferase (reaction 1, see Figure 1), and in neonatal tyrosinemia, due to lowered activity of p-hydroxyphenylpyruvate hydroxylase, EC 1.13.11.27 (reaction 2, see Figure 1). Therapy employs a diet low in protein.

The metabolic defect in alkaptonuriais a defective homogentisate oxidase (EC 1.13.11.5), which catalyzes reaction 3 of Figure 29–12. 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 16th century based on the observation that the urine darkened on exposure to air, alkaptonuria provided the basis for Sir Archibald Garrod’s early 20th 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 detection in 1977 in an Egyptian mummy dating from 1500 b.c.!

Phenylalanine

 Phenylalanine is first converted to tyrosine. Subsequent reactions are those of tyrosine (see Figure 1). Hyperphenylalaninemiasarise from defects in phenylalanine hydroxylase, EC 1.14.16.1 (type I, classic phenylketonuria [PKU], frequency 1 in 10,000 births), in dihydrobiopterin reductase (types II and III), or in dihydrobiopterin biosyn thesis (types IV and V) . Alternative catabolites are excreted (Figure 2). A diet low in phenylalanine can prevent the mental retardation of PKU.

Fig2. 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.

Lysine

 Removal of the ε-nitrogen of lysine proceeds via initial formation of saccharopine and subsequent reactions that also liberate the α-nitrogen. The ultimate product of the carbon skeleton is crotonyl-CoA. Circled numerals refer to the corresponding numbered reactions of Figure 3. Reactions 1 and 2 convert the Schiff base formed between α-ketoglutarate and the ε-amino group of lysine to l-α-aminoadipate-δ semialdehyde. Reactions 1 and 2 both are catalyzed by a single bifunctional enzyme, aminoadipate-δ-semialdehyde synthase (EC 1.5.1.8) whoseN-terminal andC-terminal domains contain lysine-α-ketoglutarate reductase and saccharopine dehydrogenase activity, respectively. Reduction of l-α-aminoadipate δ-semialdehyde 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). Reduction of crotonyl-CoA by crotanoyl-CoA reductase, EC 1.3.1.86, forms butanoyl-CoA:

Crotonyl-CoA + NADPH + H⁺- → butanoyl-CoA + NADP⁺

Fig3. Reactions and intermediates in the catabolism of lysine.

Subsequent reactions are those of fatty acid catabolism.

Hyperlysinemia can result from a metabolic defect in either the first or second activity of the bifunctional enzyme aminoadipate-δ-semialdehyde synthase, but only if the defect involves the second activity that is accompanied by elevated levels of blood saccharopine. 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 clinical management of these metabolic defects is to restrict dietary intake of l-lysine without producing malnutrition.

Tryptophan

 Tryptophan is degraded to amphibolic intermediates via the kynurenine-anthranilate pathway (Figure 4). Tryptophan 2,3-dioxygenase, EC 1.13.11.11 (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 3.5.1.9), produces kynurenine. Since kynureninase (EC 3.7.1.3) requires pyridoxal phosphate, excretion of xanthurenate (Figure 5) in response to a tryptophan load is diagnostic of vitamin B6 deficiency. Hartnup disease reflects impaired intestinal and renal trans port 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.

Fig4. Reactions and intermediates in the catabolism of tryptophan. (PLP, pyridoxal phosphate.)

Fig5. Formation of xanthurenate in vitamin B6 deficiency. Conversion of the tryptophan metabolite 3-hydroxykynurenine to 3-hydroxyanthranilate is impaired (see Figure 4). A large portion is therefore converted to xanthurenate.

Methionine

 Methionine reacts with ATP forming S-adenosylmethionine, “active methionine” (Figure 6). Subsequent reactions form propionyl-CoA (Figure 7), whose conversion to succinyl-CoA occurs via reactions 2, 3, and 4 of Figure 8.

Fig6. Formation ofS-adenosylmethionine.~ CH3 represents the high group transfer potential of “active methionine.”

Fig7. Conversion of methionine to propionyl-CoA.

Fig8. Metabolism of propionate.

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مواضيع ذات صلة

Metabolic Disorders of Branched-chain Amino Acid Catabolism

The Initial Reactions are Common to all Three Branched-Chain Amino Acids

Catabolism of Glycine, Serine, Alanine, Cysteine, Threonine, & 4-Hydroxyproline

Transamination Typically Initiates amino acid Catabolism

Metabolic Disorders are Associated with Each Reaction of The Urea Cycle

Amino Acid Oxidases Remove Nitrogen as Ammonia

Biosynthesis of Urea

Interorgan Exchange Maintains Circulating Levels of Amino Acids

ATP & Ubiquitin-Dependent Degradation

Biosynthesis of the Nutritionally Nonessential Amino Acids

Nutritionally Essential & Nutritionally Nonessential Amino Acids

Cholesterol Synthesis, Transport, & Excretion: Clinical Aspects