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

Abstract

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...

A novel mechanism in control of human pigmentation by β-melanocyte-stimulating hormone and 7-tetrahydrobiopterin

“…Given the above circumstances, it is tempting to conclude that the 7-isomer originates from the TH reaction after uptake of cytosolic 6BH 4 into melanosomes. In this context it is important to recognise that TH does require 6BH 4 while 7BH 4 fails to act as a co-factor or inhibitor for this reaction (Davis et al 1992). Our results demonstrated that 7BH 4 is a potent inhibitor of tyrosinase with mixed inhibition kinetics (Fig.…”

“…The recycling of 6BH 4 is under the control of pterin-4a-carbinolamine dehydratase (EC 4·2·1·96; PCD) and dihydropteridine reductase (EC 1·6·99·7; DHPR) (Thöny et al 2000). In the absence of a functionally active PCD enzyme, the 7-isomer of 6BH 4 is formed from non-enzymatic re-arrangement of the intermediate 4a-carbinolamine (Curtius et al 1990a,b, Davis & Kaufman 1991, Davis et al 1992. Elevated levels of 7BH 4 were first described by Curtius and colleagues in patients with a variant form of phenylketonuria (Curtius et al 1988(Curtius et al , 1990b.…”

Structure and function of PCD/DCoH, an enzyme with regulatory properties

“…Certain human diseases like a mild form of hyperphenylalaninemia [9] and the depigmentation disorder vitiligo [10] are linked to a lack or deficiency of PCD activity. This leads to an accumulation of 7-substituted pterins, which act as inhibitors of PAH [11] and thereby interfere with the phenylalanine catabolism and the biosynthesis of melanin pigments.…”

The Skin And Plasma Antioxidant Enzyme Activities In Patients With Vitiligo

“…This metabolic impairment might lead to an accumulation of H 2 O 2 within the epidermis and to the consequent oxidation of (6R)-5,6,7,8-tetrahydrobiopterin, the essential cofactor of phenylalanine hydroxylation reaction, to 6-biopterin, which is toxic to human melanocytes. [19] Davis et al [20,21] established previously that the inhibition of phenylalanine hydroxylase causes the release of H 2 O 2 due to the instability of the 4a-peroxytetrahydrobiopterin intermediate in the catalytic cycle. It is possible that the inhibition of phenyl alanine hydroxylase via H 2 O 2 yields a decreased L-tyrosine pool with an altered melanin biosynthesis in vitiligo melanocytes.…”