Tyrosinemia

Figure 30-12. Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (a-KG, a-ketoglutarate Glu, glutamate PLP, pyridoxal phosphate.) Circled numerals represent the probable sites of the metabolic defects in type II tyrosinemia neonatal tyrosinemia alkaptonuria and 0 type I tyrosinemia, or tyrosinosis.

The probable metabohc defect in type I tyrosine-mia (tyrosinosis) is at himarylacetoacetate hydrolase (reaction 4, Figure 30-12). 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 aminotransferase (reaction 1, Figure 30-12), and in neonatal tyrosinemia, due to lowered y>-hydroxyphenylpyruvate hydroxylase activity (reaction 2, Figure 30-12). Therapy employs a diet low in protein. 

Figure 32, Chromatograms of plasma and urine samples with various abnormalities, A, Phenylalaninemia B, tyrosinemia C, elevated plasma methionine seen in homocystinuria D, glycinemia E, normal urine F, argininosuccinic aciduria G, homocystinuria H, hyperglycinuria I, hyperlysinuria.

Leptospermone (34) Nitisinone (35) P Triketone Hereditary tyrosinemia type 1... 

Leptospermone (34), a representative of an important new class of herbicides from the bottlebrush plant, Callistemon citrinus (Curtis) Skeels, has been found to have an inhibitory effect on the enzyme, -hydroxyphenylpyruvate dioxygenase (HPPD), involved in the synthesis of plastoquinone in plants. Nitisinone (35), a synthetic derivative of (34), has recently been introduced to the market for the treatment of hereditary tyrosinemia type 1 (HT-1), a severe genetic disease caused by a deficiency of fumaryl acetoacetate hydrolase (FAH). ... 

Nitisinone is a reversibile inhibitor of 4-hydroxy-phenylpyruvate oxidase, an enzyme that plays a crucial role in the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxic metabolites fumaryl acetoacetate, succinyl acetoacetate and succinyl acetone. Nitisinone is used for the treatment of hereditary tyrosinemia type 1. After oral administration bioavailability is 90% and peak levels are reached at 2.5 hours after dosing. The drug is eliminated mainly in the urine but some CYP3A4-mediated metabolism seems to occur. The elimination half-life is 45 hours. Blood dyscrasias are frequently occurring side effects as are eye problems like conjunctivitis, corneal opacity and keratitis. Exfoliative dermatitis, erythematous rash and pruritus... 

Nitisinone is an inhibitor of 4-hydroxyphenyIpyruvate dehydrogenase (4-HPPD). Originally studied as a herbicide, it is now marketed to prevent hepatic damage caused by hereditary tyrosinemia type I. This genetic disease is due to the absence in the body of fumarylacetoacetase, which ensures the last step of tyrosine degradation (Figure 8.86). 

Tyrosinemia type 1 p Tyrp, Metp u all AA, -aminolevulinec acid p... 

SAH hydrolase deficiency CBS deficiency Tyrosinemia type 1 Liver disease Severe protein malnutrition... 

Tyrosine Tyrosinemia type 1,2,3 Liver disease Prematurity PKU... 

The 2-oxoacid p-hydroxyphenylpyruvate is decar-boxylated by the action of a dioxygenase (Eq. 18-49). The product homogentisate is acted on by a second dioxygenase, as indicated in Fig. 25-5, with eventual conversion to fumarate and acetoacetate. A rare metabolic defect in formation of homogentisate leads to tyrosinemia and excretion of hawkinsin97 a compound postulated to arise from an epoxide (arene oxide) intermediate (see Eq. 18-47) which is detoxified by a glutathione transferase (Box 11-B). 

Figure 20.22 Catabolism of phenylalanine and tyrosine. A indicates the lesion in classic phenylketonuria B indicates a tyrosinemia caused by tyrosine transaminase deficiency C indicates a tyrosinemia caused by p-hydroxyphenylpyruvate oxidase deficiency and the lesion in neonatal tyrosinemia D indicates alcaptonuria.

Additional errors of phenylalanine and tyrosine metabolism include tyrosinosis, or hereditary tyrosinemia, neonatal tyrosinemia, and alcaptonuria. In the first case, there is a probable defect in p-hydroxyphenylpyruvate oxidase. In neonatal tyrosinemia, the problem is transient and may be solved by the administration of ascorbic acid. Ascorbic acid is apparently a cofactor for p-hydroxy-phenylpyruvate oxidase. Alcaptonuria is a benign disorder in which homogen-tisic acid oxidase is inoperative and homogentisic acid is excreted in the urine. Air oxidizes the homogentisic acid to a pigment, giving urine a black color. This pigment also accumulates in the patient s tissues. 

A very simple triketone has proven useful for treating the rare genetic disease tyrosinemia. The drug alternately known as nitisinone (30) or orfadin actually hears a very close relation to a pesticide. The analogue in which methylsulfonyl replaces the trifluoromethyl group, mesotrione, is an important corn herbicide. Acylation of cyclohexan-l,3-dione, shown as an enol (28) with acid chloride (29), leads in a single step to 30. ... 

C-8) (C-10) Tyrosinemia. There are enzyme defects at steps in the metabolism of tyrosine. These result in the accumulation of tyrosine and its metabolites in the urine and serum. Liver and kidney dysfunction, and mental retardation are common. The condition may be treated by lowering tyrosine and phenylalanine intake. Vitamin C may be helpful as it is a cofactor for hydroxyphenylpy-ruvate hydroxylase at this step. 

Tyrosinemia Various enzymes of tyrosine degradation Weakness, self-mutilation, liver damage, mental retardation... 

D.L. Hereditary tyrosinemia type I (chronic form) Pathologic findings in the liver. Hum. Path. 1989 20 149-158... 

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