The Role of Tetrahydrobiopterin in Aromatic Amino Acid Hydroxylases

Most aromatic hydroxylases are either cytochrome- or flavin-dependent enzymes; the three enzymes that catalyze hydroxylation of the aromatic ami-no acids phenylalanine, tyrosine, and tryptophan are apparently unique in

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

utilizing tetrahydrobiopterin, which acts as a reducing substrate rather than a coenzyme. They are monooxygenases; one atom of oxygen is incorporated into the substrate as a hydroxyl group, and the other is reduced to water.

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=O 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; dihydro-folate 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, whichinvolves a defect of phenylalanine hydroxylase, responds well to dietary restriction of phenylalanine. However, so-called malignant or atypical phenylketonuria involves either a defect in dihydrobiopterin reductase, or a failure of biopterin biosynthesis. In either case, there are disturbances of phenylalanine, tyrosine, and tryptophan metabolism, and deficits of catecholamines and 5-hydroxy-tryptamine, as well as in dopamine release and nitric oxide formation (Section 10.4.2) so that the neurological problem is more serious than in classical phenylketonuria. Dietary restriction of phenylalanine has little beneficial effect, and there seems to be little that can be done forpatients with dihydrofolate reductase deficiency. For patients whose problem is an inability to synthesize biopterin, the outlook is good because synthetic biopterin derivatives are well utilized.

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