Fumarylacetoacetate hydrolase

Tyrosmaemia type I is very rare (incidence 1 100,000 births). It is caused by an autosomal recessive defect of fumarylacetoacetate hydrolase (localized on chromosome 15 q 23 — 25), which impairs tyrosine degradation. Tyrosine metabolites accumulate at the point where the metabolic process is compromised. This results in either an acute clinical course initiated immediately after birth and usually leading to a quick death or a chronic course in which patients reach adult age. (160, 161, 163, 164)... 

Tyrosinosis is presumably due to fumarylacetoacetate hydrolase deficiency and has a high prevalence in the French-Canadian population of Quebec. It is associated with abnormal liver function, renal tubular dysfunction, anemia, and vitamin D-resistant rickets. Transient tyrosinemia of the newborn, particularly in premature infants, is the most common form of tyrosinemia in infancy. 

Tyrosine Fumarylacetoacetate hydrolase Fumarylacetoacetate Tyrosinemia 1 Liver failure, death early... 

Fig. 20.1 Major catabolic pathway for phenylalanine and tyrosine. The loci of known enzymatic defects are indicated by dashed lines. Note that hereditary tyrosinemia is now believed to be due to fumarylacetoacetate hydrolase, the final step in the pathway. (Redrawn with modifications from Mazur A, Harrow B Textbook of Biochemistry. WB Saunders, Philadelphia, 1971)...

Tyrosinemia type I Fumarylacetoacetate hydrolase Increased blood phenylalanine and tyrosine increased alpha-fetoprotein urinary succinylacetone Liver failure rentil tubular acidosis, failure to thrive, vomiting, diarrhea, rickets, porphyria-like crises, hepatic carcinoma Phenylalanine and tyrosine restriction (diet used in conjunction with NTBC or until liver transplantation is possible) None... 

Fumarylacetoacetate is split to fumarate and acetoacetate by an enzyme that was known previously to hydrolyze diketo acids. It has been called acylpyruvase, triacetic acid hydrolyzing enzyme, and /J-diketonase. Since both the rate of hydrolysis of fumarylacetoacetate and its affinity for the enzyme exceed those of other substrates there is some justification for the name fumarylacetoacetate hydrolase. The irreversible action of this enzyme results in the formation of products that are metabolized by the systems previously described for fatty acid oxidation and the Krebs cycle. 

Nitisinone (26, Orfadin ) is the first drug approved in Europe for the treatment of hereditary tyrosinemia type 1 (HT-1), a rare genetic metabolic disorder caused by a deficiency of fumarylacetoacetate hydrolase (FAH), an enzyme involved in the metabolism of tyrosine [69]. Nitisinone is a derivative of leptospermone (27), an effective herbicide present in the bottlebrush... 

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