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Biosynthesis of Tetrahydrobiopterin in Man

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Biosynthesis of Tetrahydrobiopterin in Man J. tnher. Metab. Dis. 8 Suppl. 1 (I985) 28-33 Biosynthesis of Tetrahydrobiopterin in Man H.-CH. CURTIUS, D. HEINTEL, S. GHISLA1, TH. KUSTER, W. LEIMBACHER and A. NIEDERWIESER Division of Clinical Chemistry, Department of Pediatrics, University of Zurich, Switzerland t Department of Biology, University of Constance, POB 5560, D-7750 Constance, FRG The biosynthesis oftetrahydrobiopterin (BH4) from dihydroneopterin triphosphate (NHzP3) was studied in human liver extract. The phosphate-eliminating enzyme (PEE) was purified ~ 750-fold. The conversion of NH2P3 to BH~ was catalyzed by this enzyme in the presence of partially purified sepiapterin reductase, Mg z ÷ and NADPH. The PEE is heat stable when heated at 80 °C for 5 min. It has a molecular weight of 63 000 daltons. One possible intermediate 6-(l'-hydroxy-2'-oxopropyl)5,6,7,8-tetrahydropterin(2'-oxo-tetrahydro- pterin) was formed upon incubation of BH4 in the presence of sepiapterin reductase and NADP ÷ at pH 9.0. Reduction of this compound with NaBD4 yielded monodeutero threo and erythro-BH4, the deuterium was incorporated at the 2' position. This and the UV spectra were consistent with a 2'-oxo-tetrahydropterin structure. Dihydrofolate reductase (DHFR) catalyzed the reduction of BH2 to BH4 and was found to be specific for the pro-R-NADPH side. The sepiapterin reductase catalyzed the transfer of the pro-S hydrogen of NADPH during the reduction of sepiapterin to BHa. In the presence of crude liver extracts the conversion of NHzP3 to BH4 requires NADPH. Two deuterium atoms were incorporated from (4S-2H)NADHP in the 1' and 2' position of the BH4 side chain. Incorporation of one hydrogen from the solvent was found at position C(6). These results are consistent with the occurrence of an intramolecular redox exchange between the pteridine nucleus and the side chain and formation of 6-pyruvoyl-5,6,7,8-tetrahydropterin(tetrahydro-l'-2'- dioxopterin) as intermediate. Despite the numerous studies carried out on tetrahydro- of BH4, only the structures of GTP, NH2P3 and BH4 biopterin (BH4) biosynthesis in mammals, several have been established beyond doubt, as shown in Figure controversial aspects still have to be clarified (Levine et 1. Current discussions and controversies deal mainly al., 1983a; Ghisla et al., 1984). BH4 is a cofactor for with the steps leading from NHzP3 to BH4. phenylalanine, tryptophan and tyrosine hydroxylases, Tanaka et al. (1981) reported that in chicken kidney, and it has been suggested that it also plays an important NHzP3 is converted through some intermediate "x" to role in the regulation of the synthesis of biogenic amine L-sepiapterin by a heat stable, magnesium-dependent neurotransmitters (Levine et al., 1983b). Errors in BH4 "fraction A2". It was suggested that"x" was converted to biosynthesis and metabolism have been extensively studied in the rare childhood disease BH4-deficient 0 hyperphenylalaninaemia, alternatively referred to as GUANOStNE H~'Nx~ atypical phenylketonuria (Niederwieser et al., 1982), as TRtPHOSPHATE H2 N"~N ";"~? well as in certain neurological and psychiatric disorders (GTP] t (Curtius et al., 1982, 1983). The urinary excretion of P OCS O..\l neopterin (a metabotite of an intermediate in BH4 biosynthesis) has been shown to be elevated in certain OH OH diseases where there is an alteration in the status of the "CYCLOHYDROLASE" immune system (Wachter et al., 1983). A complete understanding of the enzymatic steps in the BH4 DIHYDRO- HNO/.,_y ~. ~-.HOHr---m biosynthesis in man is therefore of great importance. NEOPTERIN H2NIL.~NiL ~P3 The first reaction in mammalian BH~ biosynthesis TRIPHOSPHATE H D-ERYTHRO involves the conversion of GTP to dihydroneopterin (NH2P3) triphosphate (NH2P3) by a single enzyme, GTP J"SYNTHETASE(S)" cydohydrotase I. This has been reported in non- 2 NAD(P)H I,,REDUCTASE(S). mammalians by Fan and Brown (1976) in Drosophila and by our group in humans (Blau and Niederwieser, TETRAHYDRO- 1983). We developed an enzyme assay for GTP BIOPTERIN HN cyclohydrolase I in haman liver biopsies and lympho- (BH4) H2N~,~NI~[,..N ~ OH6H' -' cytes and reported the first patient with GTP H L-ERYTHRO cyclohydrolase deficiency (Niederwieser et al., 1984a). Figure I Biosynthesis oftetrahydrobiopterin from guanosine While the conversion of GTP to NH2P3 is catalyzed by a triphosphate. Note that only the structure of the molecules single enzyme in mammals, the further transformation of shown have been established beyond doubt. The parts of the NH2P3 to BH~ is likely to involve several enzymes. It molecules of NHzP3 which are subjected to reduction are should be pointed out that up to now in the biosynthesis denoted by squares, those which undergo inversion by circles 28 Journal of Inherited Metabolic Disease. ISSN 0141-8955. Copyright ~ SSIEM and MTP Press Limited, Queen Square, Lancaster, UK. Printed in The Netherlands. Biosynthesis of Tetrahydrobiopterin in Man 29 sepiapterin by the heat labile "fraction AI" which was (b) Inversion: Two basically distinct types of bio- reported to be NADPH-dependent, and that "x" was a chemical inversions at chiral centers are known. One type diketo-dihydropterin. of inversion can be induced directly by two enzyme active Regarding the potential of NADPH dependency of center bases and proceeds over a carbanionic transient. the sepiapterin formation from NHzP3, reported by Alternatively, and as is likely to occur in our case, redox some authors, it is puzzling that NADPH should be catalysis is involved and inversion could proceed via a considered necessary since there is no net difference in planar sp 2 carbon center (Figure 3). the redox balance between NH2P3 and sepiapterin (c) Reduction: The difference in redox state between (Heintel et al., 1984). Recently, however, we showed that NH2P3 and BH4 is 4e-. Reduction of the C(6)-N(5) NADPH is not necessary in human and vertebrates for imine might, at first sight, be considered a normal sepiapterin formation. NH2P3 was shown to be hydrogenation reaction, such as those catalyzed by converted to sepiapterin without addition of NADPH as pyridine nucleotide or flavin enzymes. In the case when well as under conditions that ensured the destruction of an intramolecular rearrangement reaction takes place, a endogenous, free NADPH (Heintel et al., 1984). Our keto-group in the 1' position must be reduced (see results have also indicated that sepiapterin may not be Figure 10). The formal reduction at C(3'), on the other an intermediate on the pathway leading to BH4 hand, might involve a more complicated set of events, i.e. biosynthesis under normal in vivo conditions. triphosphate elimination to form an enol, ketonization Duch et at. (1983) demonstrated the formation of BH4 of the latter and finally reduction of the 2'-keto group in the presence of sufficient methotrexate to inhibit thus formed. The sequence of these events, elimination, dihydrofolate reductase (DHFR) (EC 1.6.99.7) com- intramolecular oxidoreduction reaction, inversion, and pletely. This implied that sepiapterin is not on the reduction of the keto-groups, is not established. biosynthetic pathway. This was also confirmed by Elimination can be an early event and has been Milstien and Kaufman (1983) and ourselves (Heintel et proposed by Krivi and Brown (1979) to initiate the al., 1984). Together with the groups of Kaufman, Nichol conversion. Milstien and Kaufman (1983), on the other and Brown, we suggested the occurrence of internal hand, proposed that the sequence starts with the internal oxidoreduction reactions leading to tetrahydropterins redox reaction. without the need ofNADPH (Heintel et al., 1984; Levine Concerning biosynthesis, the following questions are et al~, 1983a). This process appears to be thermodynami- still unclear: cally feasible (Ghista et al., 1984). (1) How is L-biopterin formed from D-neopterin with A comparison of the chemical structures of NHzP3 inversion of two chirat centers at 1' and 2'? (see Figure and BH4 reveals that three distinct chemical transfor- 1). mations are required for their interconversion (see (2) Are quinonoid intermediates or dihydropteridine Figure 1): (a) elimination, (b) inversion, (c) reduction. reductase (DHPR) involved in the biosynthesis? (a) Elimination: The elimination of a leaving group (3) Is the tetrahydro form of the pterin nucleus such as (tri)phosphate is a facile chemical reaction formed by an intramolecular redox rearrangement? requiring a base which catalyzes the abstraction of the (4) What is the mechanism of the reduction steps? C(2')-H as a proton. Several enzymes catalyzing Does direct transfer of NADPH hydride occur ? If yes, phosphate elimination reactions are known, and the from which (R or S) side? requirement for Mg 2÷ in reactions involving organic (5) What is the role of sepiapterin reductase in the phosphates has been documented. During the reaction biosynthesis of BH4. Can it be confirmed that folate one proton from the solvent is introduced in the 3' reductase is not involved? position. However, a proton shift occurring at an active To clarify these questions we investigated the site shielded from H + exchange with solvent has also biosynthesis with stereospecific deuterium labeled been proposed. This is shown in Figure 2. Whether, as in pyridine nucleotides. our case, such a shift occurs or not can be verified experimentally. Conservation of the t' or of the 2' hydrogens in the Y-CH3 of BH, would be consistent with such hypothesis. Conversely, incorporation of i) B(x-~ !~ ~BFx_. (labeled) solvent hydrogen at C(3') would clearly exclude this type of mechanism. A possible enzyme t~ H/X R1 .XH catalyzing this conversion has been proposed by Tanaka [- - 2 et al. (1981), and is referred to as "fraction A2" which has been shown to require Mg 2+ for activity. ii) H I (-2ee). R (*2ee) R~,.C/ .XH R2 OH OP<o ,1"OrH H~O 0 H°/° c-x. - R --@CH2--rbp3 = R--C--CH2 R1 R2 (2H®) R2 (2H®) H d_ BH ÷o Figure 3 Biochemical mechanisms of inversion at chiral centers.
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