Intermediates in the enzymic synthesis of tetrahydrobiopterin in Drosophilamelanogaster

Switchenko, Arthur C.; Primus, J. P.; Brown, Gene M.

doi:10.1016/s0006-291x(84)80171-0

Cited by 56 publications

(29 citation statements)

References 9 publications

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“…The precise origin of the sepiapterin remains obscure. In Drosophila melanogaster it has been proposed that sepiapterin may arise by air oxidation of the 6-lactoyl-H 4 pterin, which lies on the H 4 biopterin pathway (53,60). Another possibility is that it could be formed from 6-pyruvoyl-H 4 pterin or 6-lactoyl-H 4 pterin under enzymatic control, e.g.…”

Section: Discussionmentioning

confidence: 99%

Development of the Pteridine Pathway in the Zebrafish,Danio rerio

Ziegler¹,

McDonald²,

Heßlinger³

et al. 2000

Journal of Biological Chemistry

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In the zebrafish, the peripheral neurons and the pigment cells are derived from the neural crest and share the pteridine pathway, which leads either to the cofactor tetrahydrobiopterin or to xanthophore pigments. The components of the pteridine pattern were identified as tetrahydrobiopterin, sepiapterin, 7-oxobiopterin, isoxanthopterin, and 2,4,7-trioxopteridine. The expression of GTP cyclohydrolase I activity during the first 24-h postfertilization, followed by 6-pyruvoyl-5,6,7,8-tetrahydropterin synthase and sepiapterin reductase, suggest an early supply of tetrahydrobiopterin for neurotransmitter synthesis in the neurons and for tyrosine supply in the melanophores. At 48-h postfertilization, sepiapterin formation branches off the de novo pathway of tetrahydrobiopterin synthesis. Sepiapterin, via 7,8-dihydrobiopterin and biopterin, serves as a precursor for the formation of 7-oxobiopterin, which may be further catabolized to isoxanthopterin and 2,4,7-trioxopteridine. Neither 7,8-dihydrobiopterin nor biopterin is a substrate for xanthine oxidoreductase. In contrast, both of these compounds are oxidized at C-7 by a xanthine oxidase variant form, which is inactivated by KCN, but is insensitive to allopurinol. The oxidase and the dehydrogenase form of xanthine oxidoreductase as well as the xanthine oxidase variant have specific developmental patterns. It follows that GTP cyclohydrolase I, the formation of sepiapterin, and the xanthine oxidoreductase family control the pteridine pathway in the zebrafish.

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Section: Discussionmentioning

confidence: 99%

Development of the Pteridine Pathway in the Zebrafish,Danio rerio

Ziegler¹,

McDonald²,

Heßlinger³

et al. 2000

Journal of Biological Chemistry

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“…compound (compound x); our group (Heintel et al, 1984), Smith and Nichol (1983), Milstien and Kaufman (1983), as well as Brown (Switchenko et al, 1984) suggested a tetrahydromono or diketo pterin as intermediate. Recently, Smith and Nichol (1984) and Switchenko et al (1984) published electrochemical data and a u.v.…”

Section: Curtius Et Almentioning

confidence: 85%

“…Recently, Smith and Nichol (1984) and Switchenko et al (1984) published electrochemical data and a u.v. spectrum in favour of a tetrahydro compound without, however, proposing any chemical structure.…”

Section: Curtius Et Almentioning

confidence: 99%

“…spectrum in favour of a tetrahydro compound without, however, proposing any chemical structure. They also claimed that there might be two NADPHdependent reductases to reduce the keto compounds (Switchenko et al, 1984;Smith and Nichol, 1984). In analogy with the oxidation of BH 2 to sepiapterin in the presence ofNADP and sepiapterin reductase at pH 9.0, we attempted the dehydrogenation of BH 4 with sepiapterin reductase from human liver and rat erythrocytes as well as with crude homogenate from human liver (Figure 4).…”

Section: Curtius Et Almentioning

confidence: 99%

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Biosynthesis of tetrahydrobiopterin in man

Curtius

Heintel

Ghisla

et al. 1985

J of Inher Metab Disea

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The biosynthesis oftetrahydrobiopterin (BH 4 ) from dihydroneopterin triphosphate (NH lP 3 ) was studied in human liver extract. The phosphate-eliminating enzyme (PEE) was purified ~ 750-fold. The conversion of NH lP, to BH 4 was catalyzed by this enzyme in the presence of partially purified sepiapterin reductase. Mg1 -and NADPH. The PEE is heat stable when heated at 80 "C for 5 min. It has a molecular weight of 63 OOU daltons. One possible intermediate 6-( I'-hydroxy-2 '-oxopropyl )5.6. 7.8-tetrahydropterin( 2' -oxo-tetrahydropterin I was formed upon incubation of BH 4 in the presence of sepiapterin reductase and NADP T at pH 9.0. Reduction of this compound with NaBD 4 yielded monodeutero threo and erythro-BH 4 • the deuterium was incorporated at the 2' position. This and the UV spectra were consistent with a 2'-oxo-tetrahydropterin structure. Dihydrofolate reductase (DHFR I catalyzed the reduction of BH l to BH 4 and was found to be specific for the pro-R-NADPH side. The sepiapterin reductase catalyzed the transfer of the pro-S hydrogen of • NAD PH during the reduction of sepiapterin to BH 1. In the presence of crude liver extracts the conversion of NH1P, to BH 4 requires NADPH. Two deuterium atoms were incorporated from (4S-1 H INADHP in the I' and 2' position of the BH 4 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-1 '-2 '-dioxopterin) as intermediate.

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“…The mammalian tunnel-fold enzyme 6-pyruvoyltetrahydropterin (PPH 4 ) 4 synthase (mPTPS) is required for the biosynthesis of 6R-L-erythro- 5,6,7, ) in eukaryotes ( Fig. 1) (3).…”

mentioning

confidence: 99%

Biochemical and Structural Studies of 6-Carboxy-5,6,7,8-tetrahydropterin Synthase Reveal the Molecular Basis of Catalytic Promiscuity within the Tunnel-fold Superfamily

Miles

Roberts

McCarty

et al. 2014

Journal of Biological Chemistry

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Background:The bacterial homolog, 6-carboxy-5,6,7,8-tetrahydropterin synthase, of the eukaryotic 6-pyruvoyltetrahydropterin synthase enzyme acts on the same substrate but produces different products. Results: Structural and biochemical studies trace the differential reactivity to four residues. Conclusion: Differential reactivity between the enzyme homologs is a result of small changes in the enzyme active site. Significance: This work furthers our understanding of how novel activities may arise from common protein-folds.

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Intermediates in the enzymic synthesis of tetrahydrobiopterin in Drosophilamelanogaster

Cited by 56 publications

References 9 publications

Development of the Pteridine Pathway in the Zebrafish,Danio rerio

Development of the Pteridine Pathway in the Zebrafish,Danio rerio

Biosynthesis of tetrahydrobiopterin in man

Biochemical and Structural Studies of 6-Carboxy-5,6,7,8-tetrahydropterin Synthase Reveal the Molecular Basis of Catalytic Promiscuity within the Tunnel-fold Superfamily

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