P-Hydroxyphenylpyruvate hydroxylase

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. 

Ascorbate increases the activity of hydroxylases needed for the conversion of p-hydroxyphenylpyruvate to homogentisate (Chapter 17), synthesis of norepinephrine from dopamine (Chapter 32), and two reactions in carnitine synthesis (Chapter 18). It is not known whether decreased activity of these enzymes contributes to the clinical characteristics of scurvy. Although ascorbic acid is needed for maximal activity of these enzymes in vivo and in vitro, most show some activity when other reducing agents are used. 

Phenylalanine hydroxylase is like p-hydroxyphenylpyruvate oxidase (see below) in its requirement for two enzyme components. It is particularly interesting that one of these components (Fraction II) can be replaced by acetone powder extracts of liver from rabbit, calf, dog, and pig, and by acetone powder extracts of kidney and heart from calf and hog, although these oi ans contain no phenylalanine hydroxylase activity. Fraction II appears to be wide distributed, and to have fimctions other than these connected with phenylalanine hydroxylation. Although two enzyme components are involved in the system, no evidence for an intermediate between phenylalanine and tyrosine has been found (557), nor has it been possible to separate the process into two steps. 

---