Phenylketonuria Dihydropteridine

FIGURE 40-2 The phenylalanine hydroxylase (PAH) pathway. Phenylketonuria usually is caused by a congenital deficiency of PAH (reaction 1), but it also can result from defects in the metabolism of biopterin, which is a cofactor for the hydroxylase. Enzymes (1) Phenylalanine hydroxylase (2) Dihydropteridine reductase (3) GTP cyclohydrolase (4) 6-pyruvoyltetrahydrobiopterin synthase. BH4, tetrahydrobiopterin DEDT, o-erythro-dihydroneopterin triphosphate QH2, dihydrobiopterin. 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway. The electron donor for phenylalanine hydroxylase is tetrahydrobiopterin (BH4), which transfers electrons to molecular oxygen to form tyrosine and dihydrobiopterin (QH2 Fig. 40-2 reaction 2). BH4 is regenerated from QH2 in an NADH-dependent reaction that is catalyzed by dihydropteridine reductase (DHPR), which is widely distributed. In the brain, this... 

A Fig. 6.1.7a- HPLC of pterins using a column-switching system a standard mixture b control urine c urine guanosine triphosphate cyclohydrolase I (GTPCH) deficiency d urine 6-pyru-voyl-tetrahydropterin synthase (PTPS) deficiency e urine pterin-4a-carbinolamine dehydratase (PCD) deficiency f urine dihydropteridine reductase (DHPR) deficiency g urine phenylketonuria 4-8 h after tetrahydrobiopterin (BH4) administration h-k see next page... 

Extrapyramidal symptoms developed with co-trimox-azole in a girl with dihydropteridine reductase deficiency and rapidly disappeared after withdrawal. This variant of phenylketonuria should be considered in all infants found to have raised phenylalanine concentrations during the neonatal period (46). 

Deficiency of phenylalanine hydroxylase, tetrahydrobiopterin, or dihydropteridine reductase results in phenylketonuria (PKU), an autosomal recessive trait. Because phenylalanine accumulates in tissues and plasma (hyperphenylalaninemia), it is metabolized by alternative pathways and abnormal amounts of phenylpyruvate appear in urine (Figure 17-22). Phenylalanine hydroxylase deficiency may be complete (classic PKU, type 1) or partial... 

The provision of reducing equivalents to phenylalanine hydroxylase is dependent on reduction of dihydrobiopterin by NADH catalyzed by the enzyme dihydropteridine reductase, as shown in Figure 38-2. This reduction is dependent on the availability of biopterin and therefore on the biopterin synthetic pathway. Thus any genetic or protein folding defect in either dihydropteridine reductase or the biopterin biosynthetic enzymes would compromise the efficacy of phenylalanine hydroxylation to tyrosine resulting in hyperphenylalaninemia and also phenylketonuria resulting from inaease transamination of phenylalanine to phenylpyruvate. 

Fates of tyrosine. Tyrosine can be degraded by oxidative processes to ace-toacetate and fumarate which enter the energy generating pathways of the citric acid cycle to produce ATP as indicated in Figure 38-2. Tyrosine can be further metabolized to produce various neurotransmitters such as dopamine, epinephrine, and norepinephrine. Hydroxylation of tyrosine by tyrosine hydroxylase produces dihydroxyphenylalanine (DORA). This enzyme, like phenylalanine hydroxylase, requires molecular oxygen and telrahydrobiopterin. As is the case for phenylalanine hydroxylase, the tyrosine hydroxylase reaction is sensitive to perturbations in dihydropteridine reductase or the biopterin synthesis pathway, anyone of which could lead to interruption of tyrosine hydroxylation, an increase in tyrosine levels, and an increase in transamination of tyrosine to form its cognate a-keto acid, para-hydroxyphenylpyruvate, which also would appear in urine as a contributor to phenylketonuria. 

PKU Phenylketonuria the pathologic condition of increased excretion of phenylketones in the urine because of impaired conversion of phenylalanine to tyrosine. Classical PKU is because of a genetic deficiency of phenylalanine hydroxylase however, other causes are deficiencies in dihydropteridine reductase or in the biosynthesis of tetrahydrobiopterin. 

The results obtained using the screening techniques in mentally retarded children prompted us to try to study some inborn errors in animal models . Experimental phenylketonuria, for example, can be simulated by overloading with phenylalanine or by inhibiting the phenylalanine hydroxylase with /7-chlorophenylalanine. We have used both /w hloro-phenylalanine and esculin (to block the dihydropteridine reductase reaction), a treatment which leads to a complete inhibition of the enzyme< > > (Fig. 2). 

---