Phenylalanine hydroxylase cofactor

Pyrimidine-2,4-diamine, 5-(benzylamino)-6-hydroxy-as cofactor of phenylalanine hydroxylase, 1, 261 Pyrimidine-2,4-diamine, 5-ethoxy-synthesis, 3, 114... 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway 673... 

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... 

Phenylalanine hydroxylase (PH) which requires tetrahydrobiopterin (BH4) as a cofactor, is defective in cases of phenylketonuria (PKU). This is a rare (prevalence 1 / 15 000 in the United Kingdom) genetic condition characterized by fair complexion, learning difficulties and mental impairment. If PH is either not present in the hepatocytes or is unable to bind BH4 and is therefore non functional, phenylalanine accumulates within the cells. Enzymes in minor pathways which are normally not very active metabolize phenylalanine ultimately to phenylpyruvate (i.e. a phenylketone). To use the traffic flow analogy introduced in Chapter 1, the main road is blocked so vehicles are forced along side roads. Phenylpyruvate is excreted in the urine (phenyl-ketone-uria), where it may be detected but a confirmatory blood test is required for a reliable diagnosis of PKU to be made. 

Phe Tyr (phenylalanine hydroxylase, biopterin cofactor) Met homoCys + Ser cystathionine Cys... 

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+Oj B tyrosine hydroxylase+ tetrahydropteridme+Fe+ +Oj C=dopa decarboxylase+pyridoxal phosphate D= dopamine beta-oxidase+ascorbate phosphate+Cu+ +Oj E=phenylethanolamine N-methyltransferase+S-adenosylmethionine l=monoamine oxidase and aldehyde dehydrogenase 2=catechol-0-methyltransferase+S-adenosylmethionine.

After removal of their amino groups, the carbon skeletons of amino acids undergo oxidation to compounds that can enter the citric acid cycle for oxidation to C02 and H20. The reactions of these pathways require a number of cofactors, including tetrahydrofolate and 5-adenosylmethionine in one-carbon transfer reactions and tetrahydrobiopterin in the oxidation of phenylalanine by phenylalanine hydroxylase. 

Recently it was discovered that cofactor activity with phenylalanine hydroxylase is not limited to tetrahydropterin derivatives. Thus, the substituted pyrimidines 2,4,5-triamino-6-hydroxypyrimidine (21) and 5-(benzylamino)-2,4-diamino-6-hydroxypyrimidine (22) are active in the L-phenylalanine hydroxylating system (78BBR(85)1614, 79JBC(254)5150, 80JBC(255)7774). The amine substituent at C-5 of (21) and (22) is apparently required for... 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

Phenylalanine Hydroxylase (EC 1.14.16.1). In arene hydroxylation of phenylalanine to produce tyrosine, mammalian phenylalanine hydroxylase (PAH) requires nonheme iron and tetrahydropterin cofactor. The role of the metal is... 

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. 

Figure 19-2. Aromatic amino acid hydroxylase reaction. Aromatic amino acids are hy-droxylated by a common mechanism catalyzed by a family of hydroxylases.The enzyme family consists of phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. In addition to substrate, all three enzymes require molecular oxygen and the cofactor tetrahydrobiopterin.Tetrahydrobiopterin is consumed in this reaction and converted into pterin 4cx-carbinolamine. DOPA, dihydroxyphenylalanine.

Figure 19-6. Hypothetical active site complex of phenylalanine hydroxylase. The nonheme iron atom of phenylalanine hydroxylase is coordinated with protein amino acid residues (top of the figure) and molecular oxygen. The BH4 cofactor is also coordinated with molecular oxygen (bottom of the figure). It has been suggested that this complex decomposes to either an iron-oxygen complex or a biopterin-4 hydroperoxide complex prior to interaction with the amino acid substrate.

Teigen K, Frpystein NA, Martinez A The structural basis of the recognition of phenylalanine and pterin cofactors by phenylalanine hydroxylase implications for the catalytic mechanism. / Mol Biol 294 807-823,1999. 

The reductant here is tetrahydrohiopterin, an electron carrier that has not been previously discussed and is derived from the cofactor biopterin. Because biopterin is synthesized in the body, it is not a vitamin. Tetrahydrohiopterin is initially formed by the reduction of dihydrobiopterin by NADPH in a reaction catalyzed by dihydrofolate reductase (Figure 23.28). NADH reduces the quinonoid form of dihydrobiopterin produced in the hydroxylation of phenylalanine back to tetrahydrohiopterin in a reaction catalyzed by dihydropteridine reductase. The sum of the reactions catalyzed by phenylalanine hydroxylase and dihydropteridine reductase is... 

Phenylketonuria is perhaps the best known of the diseases of amino acid metabolism. Phenylketonuria is caused by an absence or deficiency of phenylalanine hydroxylase or, more rarely, of its tetrahydrobiopterin cofactor. Phenylalanine accumulates in all body fluids because it cannot be converted into tyrosine. Normally, three-quarters of the phenylalanine is converted into tyrosine, and the other quarter becomes incorporated into proteins. Because the major outflow pathway is blocked in phenylketonuria, the blood level of phenylalanine is typically at least 20-fold as high as in normal people. Minor fates of phenylalanine in normal people, such as the formation of phenylpyruvate, become major fates in phenylketonurics. 

In about 2% of cases, hyperphenylalaninemia is due to a deficiency of either biosynthesis or recycling of BH4, the cofactor of phenylalanine hydroxylase and related enzymes (see Figure 55-5). These infants could be diagnosed with PKU at first, but they deteriorate neurologically despite adequate dietary control. BH4 is a cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. The latter two enzymes are involved in the synthesis of the neurotransmitters dopamine and serotonin, BH4 is also a cofactor for nitric... 

Infants with benign hyperphenylalaninemia are occasionally identified because of a moderately elevated blood concentration of phenylalanine. These patients have a partial deficiency of phenylalanine hydroxylase with residual enzyme activity up to 35% of normal subjects. Although detected by neonatal screening, they remain healthy without dietary treatment once the possibility of an underlying cofactor deficiency has been ruled out. 

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