Purification and characterization of sepiapterin reductase from rat erythrocytes

Sueoka, Terumi; Katoh, Shigeo

doi:10.1016/0304-4165(82)90178-7

Cited by 71 publications

(24 citation statements)

References 28 publications

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“…These studies indicate that the salvage pathways cannot provide sufficient BH4, unlike the BH4 biosynthesis pathway catalyzed by SPR. Biochemical analysis showed that BmSPR exhibited enzymatic properties more similar to those of mammalian SPRs than to Drosophila SPR (Table 3) (21,31,32), which was consistent with a previous report (10). Collectively, the biosynthetic pathway of BH4 and the enzymatic properties of SPR are similar between Bombyx and mammals, suggesting that the silkworm is a suitable animal for studying human SPR/BH4 deficiency.…”

Section: Discussionsupporting

confidence: 91%

The Silkworm Mutant lemon (lemon lethal) Is a Potential Insect Model for Human Sepiapterin Reductase Deficiency

Meng

Katsuma

Daimon

et al. 2009

Journal of Biological Chemistry

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Tetrahydrobiopterin (BH4) is an essential cofactor for aromatic acid hydroxylases, which control the levels of monoamine neurotransmitters. BH4 deficiency has been associated with many neuropsychological disorders. An inherited defect in BH4 biosynthesis is caused by the deficiency of sepiapterin reductase (SPR), which catalyzes the biosynthesis of BH4 from guanosine triphosphate at the terminal step. The human SPR gene has been mapped at the PARK3 locus, which is related to the onset of Parkinson disease. In this study, we report that mutant strains, lemon (lem) and its lethal allele lemon lethal (lem 1 ) with yellow body coloration, of the silkworm Bombyx mori could be used as the first insect model for human SPR deficiency diseases. We demonstrated that mutations in the SPR gene (BmSpr) were responsible for the irregular body coloration of lem and lem l . Moreover, biochemical analysis revealed that SPR activity in lem l larvae was almost completely diminished, resulting in a lethal phenotype that the larvae cannot feed and that die immediately after the first ecdysis. Oral administration of BH4 and dopamine to lem l larvae effectively increased their survival rates and feeding abilities. Our data demonstrate that BmSPR plays a crucial role in the generation of BH4, and monoamine neurotransmitters in silkworms and the lem (lem l ) mutant strains will be an invaluable resource to address many questions regarding SPR and BH4 deficiencies.

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Section: Discussionsupporting

confidence: 91%

The Silkworm Mutant lemon (lemon lethal) Is a Potential Insect Model for Human Sepiapterin Reductase Deficiency

Meng

Katsuma

Daimon

et al. 2009

Journal of Biological Chemistry

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“…To substantiate the identity of sepiapterin formed from NH 2 P 3 , purified sepiapterin reductase and NADPH were added after the 15 minute reaction. After an additional 15 minutes, no sepiapterin could be detected and as expected, dihydrobiopterin was formed (Sueoka and Katoh, 1982). Thus, it is reasonable to assume that this peak at 11.5 minutes is sepiapterin.…”

Section: Resultssupporting

confidence: 62%

Biosynthesis of tetrahydrobiopterin: possible involvement of tetrahydropterin intermediates

Heintel

Ghisla²,

Curtius

et al. 1984

Neurochemistry International

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-The biosynthetic pathway of tetrahydrobiopterin (BH 4 ) from dihydroneopterin triphosphate (NH 2 P 3 ) was studied in fresh as well as heat-treated human liver extracts. The question of NAD(P)H dependency for the formation of sepiapterin was examined. NH 2 P 3 was converted by fresh extracts to sepiapterin in low quantities (2% conversion) in the absence of exogenously added NADPH as well as under conditions that ensured the destruction of endogenous, free NAD(P)H. The addition of NADPH to the fresh liver extracts stimulated the synthesis of BH 4 to a much higher yield (17% conversion), and the amount of sepiapterin formed was reduced to barely detectable levels. In contrast, the heat-treated extract (enzyme A2 fraction) formed sepiapterin (1.3% conversion) only in the presence and not in the absence of NADPH. These results indicate that sepiapterin may not be an intermediate on the pathway leading to BH 4 biosynthesis under normal~vivo conditions. Rather, sepiapterin may result from the breakdown of an as yet unidentified intermediate that is actually on the pathway. It is speculated that NH 2 P 3 may be converted to a diketo-tetrahydropterin intermediate (or an equivalent tautomeric structure) by a mechanism involving an intramolecular oxidoreduction reaction. A diketo-tetrahydropterin intermediate could be converted to 5,6-dihydrosepiapterin, which also has a tetrahydropterin ring system and can be converted directly to BH 4 by sepiapterin reductase. This proposed pathway can explain how the tetrahydropterin ring system can be formed without sepiapterin, dihydrobiopterin, or dihydrofolate reductase being involved in BH 4 biosynthesis~vivo.

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“…Bovine liver dihydrofolate reductase was from Sigma Chemical Co. Sepiapterin reductase from rat erythrocytes was partially purified by the method of Sueoka and Katoh [22], except that only the first two column steps were performed, Partially purified human liver extracts were prepared by ammonium sulfate fractionation and Sephadex G-25 chromatography as described earlier [19]. A partially purified sepiapterin reductase from human liver ( = hydroxyapatite fraction) was prepared by an adaptation of the method of Katoh and Sueoka [23].…”

Section: Enzymes and Extractsmentioning

confidence: 99%

Tetrahydrobiopterin biosynthesis. Studies with specifically labeled (2H)NAD(P)H and 2H2O and of the enzymes involved

Curtius¹,

Heintel²,

Ghisla³

et al. 1985

Eur J Biochem

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The biosynthesis of tetrahydrobiopterin from either dihydroneopterin triphosphate, sepiapterin, dihydrosepiapterin or dihydrobiopterin was investigated using extracts from human liver, dihydrofolate reductase and purified sepiapterin reductase from human liver and rat erythrocytes. The incorporation of hydrogen in tetrahydrobiopterin was studied in either 2H2O or in H2O using unlabeled NAD(P)H or (R)‐(4‐2H)NAD(P)H or (S)‐(4‐2H)NAD(P)H. Dihydrofolate reductase catalyzed the transfer of the pro‐R hydrogen of NAD(P)H during the reduction of 7,8‐dihydrobiopterin to tetrahydrobiopterin. Sepiapterin reductase catalyzed the transfer of the pro‐S hydrogen of NADPH during the reduction of sepiapterin to 7,8‐dihydrobiopterin. In the presence of partially purified human liver extracts one hydrogen from the solvent is introduced at position C(6) and the 4‐pro‐S hydrogen from NADPH is incorporated at each of the C(1′) and C(2′) position of BH4. Label from the solvent is also introduced into position C(3′). These results suggest that dihydrofolate reductase is not involved in the biosynthesis of tetrahydrobiopterin from dihydroneopterin triphosphate. They are consistent with the assumption of the occurrence of a 6‐pyruvoyl‐tetrahydropterin intermediate, which is proposed to be formed upon triphosphate elimination from dihydroneopterin triphosphate, and via an intramolecular redox reaction. Our results suggest that the reduction of 6‐pyruvoyl‐tetrahydropterin might be catalyzed by sepiapterin reductase.

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Purification and characterization of sepiapterin reductase from rat erythrocytes

Cited by 71 publications

References 28 publications

The Silkworm Mutant lemon (lemon lethal) Is a Potential Insect Model for Human Sepiapterin Reductase Deficiency

The Silkworm Mutant lemon (lemon lethal) Is a Potential Insect Model for Human Sepiapterin Reductase Deficiency

Biosynthesis of tetrahydrobiopterin: possible involvement of tetrahydropterin intermediates

Tetrahydrobiopterin biosynthesis. Studies with specifically labeled (2H)NAD(P)H and 2H2O and of the enzymes involved

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