Primapterinuria: A New Variant of Atypical Phenylketonuria

Blau, Nenad; Curtius, Hans−Christoph; Kuster, Thomas; Matasović, A.; Schoedon, Gabriele; Dhondt, Jean-Louis; Guibaud, P; Giudici, Tullio A.; Blaskovics, M.

doi:10.1007/bf03335415

Cited by 16 publications

(27 citation statements)

References 4 publications

(1 reference statement)

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“…The discovery of increased excretion of this isomer in the urine of some hyperphenylalaninemic patients (17)(18)(19), its increased excretion after a load of natural tetrahydrobiopterin (20), and the demonstration that the stereochemistry of the dihydroxypropyl side chain is identical with that of the natural cofactor (33) have led to the suggestion that 7-biopterin may be produced from 6-biopterin as a result of a genetic alteration in the phenylalanine hydroxylase system (22).…”

Section: Resultsmentioning

confidence: 99%

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Conversion of 6-substituted tetrahydropterins to 7-isomers via phenylalanine hydroxylase-generated intermediates.

Davis

Kaufman

Milstien

1991

Proc. Natl. Acad. Sci. U.S.A.

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A new variant form of hyperphenylalaninemia has recently been discovered in which the patients characteristically excrete 7-biopterin in their urines in addition to the natural 6-biopterin (Curtius, H. Ch., Kuster, T., Matasovic, A., Blau, N. & Dhondt, J.-L. (1988) Biochem. Biophys. Res. Commun. 153,[715][716][717][718][719][720][721]. This isomer had not been found previously in humans, and although its origin was not established, preliminary evidence suggested that it might be produced from 6-biopterin. We have now found that 7-biopterin can be formed in vitro from (6R)-tetrahydrobiopterin during the hydroxylation of phenylalanine catalyzed by phenylalanine hydroxylase [L-phenylalanine, tetrahydrobiopterin:oxygen oxidoreductase (4-hydroxylating), EC 1.14.16.1]. The resulting 7-biopterin was unequivocally identifiled by the following criteria: preparative isolation and conversion to 7-hydroxymethylpterin following periodate oxidation and borohydride reduction, quantitative conversion to pterin-7-carboxylic acid after oxidation with permanganate, and liquid chromatography/thermospray mass spectrometry. Addition of 4a-carbinolamine dehydratase, an enzyme involved in the regeneration of tetrahydrobiopterin from the pterin carbinolamine intermediate (also called 4a-hydroxytetrahydrobiopterin) formed in the phenylalanine hydroxylase reaction, greatly decreased the amount of the 7-biopterin formed. This result implies that the in vitro formation of 7-biopterin occurs via the nonenzymatic rearrangement of the unstable substrate of the dehydratase, 4a-hydroxytetrahydrobiopterin, and suggests that this new variant of hyperphenylalaninemia may be caused by a lack of 4a-carbinolamine dehydratase activity. A mechanism for the rearrangement is proposed that predicts that other 6-substituted tetrahydropterin substrates of the aromatic amino acid hydroxylases could also give rise to rearranged products from an opening of the pyrazine ring of the corresponding 4a-hydroxytetrahydropterin intermediate.

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Section: Resultsmentioning

confidence: 99%

“…This pterin has now been identified as 7-biopterin (19,20), an isomer of biopterin [2-amino-4-hydroxy-6-(1,2-dihydroxypropyl)pteridine or 6-biopterin]. The origin of this new isomer has been the subject of some speculation (21).…”

mentioning

confidence: 99%

Conversion of 6-substituted tetrahydropterins to 7-isomers via phenylalanine hydroxylase-generated intermediates.

Davis

Kaufman

Milstien

1991

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, several patients have been described with a mild form of hyperphenylalaninemia, who have elevated urinary levels of an isomer of BH4, 2-amino-4-hydroxy-7-[1,2-dihydroxypropyl)-(L-erythro)-5,6,7,8-tetrahydropteridine] ("7-tetrahydrobiopterin" or 7-BH4),* and somewhat decreased levels of BH4 (5). It has been suggested (6,7) that the accumulation of abnormal amounts of 7-BH4 might be the result of an alteration of the gene coding for 4a-hydroxytetrahydrobiopterin dehydratase (6,7).…”

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confidence: 99%

"7-tetrahydrobiopterin," a naturally occurring analogue of tetrahydrobiopterin, is a cofactor for and a potential inhibitor of the aromatic amino acid hydroxylases.

Davis

Ribeiro

Tipper

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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The ability of 2-amlno-4-hydroy-7-[dibydroxylpropyl-(L-erythro)-5,6,7,8-tetrahydropterinJ ("7-tetrahydroblopterin" or Hyperphenylalaninemia is an abnormality characteristic of a series of diseases that result from an inability to catalyze the first step in the catabolism of phenylalanine-namely, its conversion to tyrosine (1). The most common cause of this abnormality is the absence of active phenylalanine hydroxylase due to a defect in the gene coding for this enzyme (2, 3). Variant forms of this disease have been reported that are caused by genetic defects in either the biosynthesis of the essential pterin cofactor tetrahydrobiopterin (BH4) or its enzymatic regeneration (4). Since BH4 is required for catecholamine and serotonin biosynthesis by tyrosine hydroxylase and tryptophan hydroxylase, respectively (4), patients with these other forms of hyperphenylalaninemia also have a deficiency of biogenic amine neurotransmitters.Recently, several patients have been described with a mild form of hyperphenylalaninemia, who have elevated urinary levels of an isomer of BH4, 2-amino-4-hydroxy-7-[1,2-dihydroxypropyl)-(L-erythro)-5,6,7,8-tetrahydropteridine] ("7-tetrahydrobiopterin" or 7-BH4),* and somewhat decreased levels of BH4 (5). It has been suggested (6, 7) that the accumulation of abnormal amounts of 7-BH4 might be the result of an alteration of the gene coding for 4a-hydroxytetrahydrobiopterin dehydratase (6,7). This enzyme catalyzes the dehydration of 4a-hydroxytetrahydrobiopterin (4a-carbinolamine), the form of the pterin that is initially released from the aromatic amino acid hydroxylases after the BH4-dependent hydroxylation of their respective substrates (7-9). In vitro, 4a-carbinolamine dehydrates at a rapid rate even in the absence of the dehydratase, but a small percentage of the 4a-carbinolamine rearranges to form the 7-isomer (6, 7). Thus the dehydratase plays the dual role of catalyzing the dehydration and preventing the isomerization ofthe pterin cofactor (7).To date, the cause of the observed mild hyperphenylalaninemia in children who excrete 7-BH4 remains unclear. Among the possible reasons for this abnormality are either that the reaction catalyzed by the dehydratase becomes rate-limiting due to the absence of the enzyme or that 7-BH4 itself in some way impairs the phenylalanine hydroxylation reaction. One possible mechanism for such impairment became apparent when we showed that the oxidation of 7-BH4 by phenylalanine hydroxylase in the presence of phenylalanine is 85-90%o uncoupled from the hydroxylation of the substrate (10). In this report we demonstrate an additional mechanism by which 7-BH4 might impair phenylalanine hydroxylase activity; i.e., 7-BH4 is a potent inhibitor of this reaction. Furthermore, we have examined the effect of 7-BH4 on the reactions catalyzed by tyrosine hydroxylase and tryptophan hydroxylase and have found that although these reactions are inhibited by this pterin in vitro, the inhibition is manifested only at very high concentrations of 7-BH4.MATERLS AND METH...

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“…The aromatic amino acid hydroxylases phenylalanine hydroxylase (EC 1.14.16.1, PAH) and tyrosine hydroxylase (EC 1.14.16.2, TH) and the tryptophan hydroxylases 1 and 2 (EC 1.14.16.4, TPH1 and TPH2) are highly homologous enzymes that all use molecular oxygen and (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH 4 ], usually referred to as cofactor, as additional cosubstrates. PAH is the rate-limiting enzyme in the catabolic oxidation of the essential amino acid L-Phe.…”

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“…PAH is the rate-limiting enzyme in the catabolic oxidation of the essential amino acid L-Phe. After the PAH catalytic cycle, the functional tetrahydro form is regenerated from the resulting pterin-4a-carbinolamine (4-OH-BH 4 ) by the coupled action of pterin 4a-carbinolamine dehydratase (EC 4.1.2.96, PCD) that catalyzes the dehydration of 4-OH-BH 4 to quinonoid dihydrobiopterin (q-BH 2 ) and the NAD(P)H-dependent dihydropteridine reductase (EC 1.6.99.7 DHPR) that reduces q-BH 2 back to 6(R)BH 4 (Fig. 1).…”

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confidence: 99%

Specific interaction of the diastereomers 7(R)‐ and 7(S)‐tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo

Pey

Martı́nez²,

Charubala

et al. 2006

FASEB j.

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Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3-4.9 microM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo.

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Primapterinuria: A New Variant of Atypical Phenylketonuria

Cited by 16 publications

References 4 publications

Conversion of 6-substituted tetrahydropterins to 7-isomers via phenylalanine hydroxylase-generated intermediates.

Conversion of 6-substituted tetrahydropterins to 7-isomers via phenylalanine hydroxylase-generated intermediates.

"7-tetrahydrobiopterin," a naturally occurring analogue of tetrahydrobiopterin, is a cofactor for and a potential inhibitor of the aromatic amino acid hydroxylases.

Specific interaction of the diastereomers 7(R)‐ and 7(S)‐tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo

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