The novel biosynthetic pathway of tetrahydrobiopterin
| Project/Area Number |
14570776
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Ninon University |
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Principal Investigator |
IINO Teruhiko Ninon University, College of Humanities and Sciences, Professor, 文理学部, 教授 (50059937)
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| Co-Investigator(Kenkyū-buntansha) |
SHINTAKU Haruo Osaka City University, School of medicine, Associate Professor, 医学部, 助教授 (00206319)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | aldo-keto reductase / carbonyl reductase / BH4 deficiency / tetrahydrobiopterin / sepiaoterin reductase / SPR欠損症 / BH4生合成系 |
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| Research Abstract |
Tetrahydrobiopterin (BH_4) is a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase. The biosynthesis includes two reduction steps catalyzed by sepiapterin reductase. However, patients with sepiapterin reductase deficiency show normal urinary excretion of pterins without hyperphenylalaninemia, suggesting that other enzymes catalyze the two reduction steps. In this research, the reductase activities for the tetrahydropterin intermediates were examined using several human recombinant enzymes belonging to the aldo-keto reductase (AKR) family. In the reduction of PPH_4 by AKR family enzymes, 2'-OXPH_4 was formed by 3α-hydroxysteroid dehydrogenase type 2, whereas 1'-OXPH_4 was produced by aldose reductase, aldehyde reductase and 20α-hydroxysteroid dehydrogenase, and both 1'-OXPH_4 and 2'-OXPH_4 were detected as the major and minor products by 3α-hydroxysteroid dehydrogenases (types 1 and 3). The activities of aldose reductase and 3α-hydroxysteroid dehydrogenase type 2 (106 and 35 nmol/mg/min, respectively) were higher than those of the other enzymes (0.2-4.0nmol/mg/min). Aldose reductase reduced 2'-OXPH_4 to BH_4, but the other enzymes were inactive towards both 2-OXPH_4 and 1'-OXPH_4. These results indicate that the tetrahydropterin intermediates are natural substrates of the human AKR family enzymes and suggest a novel alternative pathway from PPH_4 to BH_4, in which 3α-hydroxysteroid dehydrogenase type 2 and aldose reductase work in concert.
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Report
(3 results)
Research Products
(9 results)
