Hydroxyphenylpyruvic hydroxylase

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. 

The metabolism of phenylalanine will now be considered in some detail, as two inborn errors of metabolism are known that affect this pathway. Phenylalanine is first hydroxylated by phenylalanine hydroxylase to form another aromatic amino acid tyrosine (Fig. 8). The coenzyme for this reaction is the reductant tetrahydrobiopterin which is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is classified as a monooxygenase as one of the atoms of 02 appears in the product and the other in HzO. The tyrosine is then trans-aminated to p-hydroxyphenylpyruvate, which is in turn converted into homogentisate by p-hydroxyphenylpyruvate hydroxylase. This hydroxylase is an example of a dioxygenase, as both atoms of 02 become incorporated into the product (Fig. 8). The homogentisate is then cleaved by homogentisate oxidase, another dioxygenase, before fumarate and acetoacetate are produced... 

The next step in the degradation of phenylalanine and tyrosine is the transamination of tyrosine to p-hydroxyphenylpyruvate (Figure 23.30). This a-ketoacid then reacts with Oj to form homogentisate. The enzyme catalyzing this complex reaction, p-hydroxyphenylpyruvate hydroxylase, is called a... 

Saito, I., Y. Chujo, H. Shimazu, M. Yamane, T. Matsuura, and H. J. Cahnmann Non Enzymic Oxidation of p-Hydroxyphenylpyruvic Acid with Singlet Oxygen to Homogentisic Acid. A Model for the Action of p-Hydroxyphenylpyruvate Hydroxylase. J. Amer. Chem. Soc. 97, 5272 (1975). 

Goswami, M.N.D., Rosenberg, A.J. and Meury, F. (1973), A comparative analysis of the ontogenic development of rat liver sequential enzymes - Tyrosine a-ketoglutarate aminotransferase, p-hydroxyphenylpyruvate hydroxylase, and homogentisate oxygenase. Dev. Biol., 30,129. 

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