Dihydrobiopterin reductase

Mild or nonclassic forms of PKU can be caused by deficiency of dihydrobiopterin reductase. 

NADPH Dihydrobiopterine reductase Biopterine-NHI Phenylalanine hydroxylase 24-27)... 

A deficiency in dihydrobiopterin reductase or dihydrobioptenn synthetase leads to hyperphenylalaninemia, and decreased synthesis of catecholamines and serotonin. 

The first step in the liver pathway is catalyzed by phenylalanine hydroxylase. Tetrahydrobiopterin is a cofactor. This redox cofactor is also required for the hydroxylation of tyrosine to form L-dopa (Chapter 16) and for the hydroxylation of tryptophan to form 5-hydroxy tryptophan. The structure of tetrahydrobiopterin is given in Figure 20.23. In the process of phenylalanine hydroxylation, the tetrahydrobiopterin is oxidized to dihydrobiopterin. The reduced form is then recovered via NADH and dihydrobiopterin reductase, as shown in Figure 20.23. Dihydrobiopterin, although similar in structure to folic acid, is synthesized in the human organism from GTP. 

A number of genetic disorders are associated with phenylalanine and tyrosine metabolism. The best known is the classic phenylketonuria, discovered in 1934 by Foiling. It is characterized by the virtual absence of phenylalanine hydroxylase from the organism. As a result, phenylalanine is converted to a large extent to phenylpyruvate, phenyllactate, and phenylacetate (Figure 20.22). Their levels and that of phenylalanine in the bloodstream are elevated. Hyper-phenylalaninemia may also result from the absence of dihydrobiopterin reductase or any enzyme required for dihydrobiopterin biosynthesis from GTP. Although the etiologies of such disorders differ from that of classic phenylke-... 

Although mutations to dihydro biopterin reductase and PAH are equally likely to be found in the population, how can you account for the observation that mutations to dihydrobiopterin reductase accounts for only about 2% of patients with PKU and HPA ... 

The first enzyme activity (dihydrobiopterin reductase) catalyzes the transfer of hydrogen to dihydrobiopterin, which is thus reduced to tetrahydrobiopterin. The second enzyme activity is a hydroxylase containing two Fe3+ atoms, and this catalyzes the reduction of Oz such that one oxygen atom is incorporated into phenylalanine to form tyrosine and the second into water. At the same time tetrahydrobiopterin is oxidized to dihydrobiopterin. Phenylalanine hydroxylase is an example of a mixed-function oxidase. An inherited deficiency of phenylalanine hydroxylase results in the accumulation of phenylalanine that is not converted to tyrosine but is excreted as phenylpyruvate. This condition, which affects young infants, is known as phenylketonuria and is associated with severe mental retardation. 

Phenylketonuria is due to an inborn error of phenylalanine metabolism. Typically, it is due to a deficiency of phenylalanine hydroxylase. Atypically, it can be caused by a deficiency of dihydrobiopterin reductase and a resultant inability to synthesize biopterin. All these conditions cause an accumulation of phenylalanine, which can be transaminated to phenylpyruvic acid. 

Figure 10.10. Role of tetrahydrobiopterin in aromatic amino acid hydroxylases. Phenylalanine hydroxylase, EC 1.14.16.1 tyrosine hydroxylase, EC 1.14.16.2 tryptophan hydroxylase, EC 1.14.16.4 and dihydrobiopterin reductase (dihydropteridine reductase), EC 1.6.99.7.

As shown in Figure 10.10, tetrahydrobiopterin activates molecular oxygen by forming a peroxypterin that reacts with an iron atom in the active site, yielding Fe=0 that reacts with the amino acid substrate, and hydroxypterin, which then undergoes dehydration to yield dihydrobiopterin. Dihydrobiopterin is reduced back to tetrahydrobiopterin by dihydrobiopterin reductase dihydrofolate reductase (Section 10.3.3) does not have any significant activity toward dihydrobiopterin (Fitzpatrick, 1999). 

The same pool of tetrahydrobiopterin and the same dihydrobiopterin reductase are involved in the central nervous system in the hydroxylation of all three aromatic amino acids. Classical phenylketonuria, which involves a defect... 

There is a long-standing myth that ascorbate is required for the hydroxy-lation of tyrosine to dihydroxyphenylalanine (see Figure 13.4) emd the similtn reactions of phenylalanine and tryptophan hydroxylases. This belief enose as a result of early studies of a nonenzymic reaction to synthesize the hydroxy-lated amino acids for further study. It becctme established that ascorbate was required for these hydroxylations, and it is still common to include it in the incubation buffer. So far from requiring ascorbate, the addition of relatively low concentrations of ascorbate to prepeuations of tyrosine hydroxylase that has been activated by cAMP-dependent protein kinase results in irreversible loss of activity, tdthough the unacdvated form of the enzyme is unaffected by ascorbate (Wilgus emd Roskoski, 1988). As discussed in Section 10.4.1, these enzymes are biopterin-dependent, and require dihydrobiopterin reductase and NADPH for activity. There is, however, evidence that, in some nerve cell lines in culture, tyrosine hydroxylase may be induced by ascorbate (Seitz et al., 1998). 

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