Study of novel biosynthetic pathway of BH_4 which concern human aldo-keto reductases
| Project/Area Number |
16591059
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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 | Nihon University |
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Principal Investigator |
IINO Teruhiko Nihon University, Graduate School of Medicine, Associate Professor, 文理学部, 教授 (50059937)
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| Co-Investigator(Kenkyū-buntansha) |
SHINTAKU Haruo Osaka City University, Graduate School of Medicine, Associate Professor, 大学院医学研究科, 助教授 (00206319)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | Tetrahydrobiopterin / Carbonyl reductase / Sepiapterin reductase / Biosynthesis of tetrahydrobioterin / Tetrahydrobiopterin deficiency / Sepiapterin reductase deficiency / AKR 1B1 / AKR1C3 / BH4生合成系 / アルド・ケト環元酵素 |
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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.
PPH_4 is reduced to 6-(1'-oxo-2'-hydroxypropyl)-tetrahydropterin (1'-OXPH_4) or 6-(1'-hydroxy-2'-oxopropyl)-tetrahydropterin (2'-OXPH_4), which is further converted to BH_4.
In 2001, sepiapterin reductase (SPR) deficiency was reported in dystonia like disease. However. patients with SPR deficiency show normal urinary excretion of pterins without hyperphenylalaninemia, suggesting the existence of another BH_4 biosynthetic pathway, which is not concerned with SPR in humans.
Recently. we reported a new SPR-unrelated BH_4 formation route from PPH_4, in which human aldo-keto reductase (AKR1C3 and AKR1B1) work in concert.. In the reduction of PPH_4 by AIM family enzymes, 2'-OXPH_4 was formed by 3α-hydroxysteroid dehydrogenase type 2(AKR1C3), whereas 1'-OXPH_4 was produced by aldose reductaseUK.R1B1), respectably.
Blau et al. proposed a BH_4 biosynthetic salvage pathway containing nonenzymatic conversion of 1'-OXPH_4 to sepiapterin. In this study, the possibility of the nonenzymatic conversion of 1'-OXPH_4 to sepiapterin was examined by using human aldo-keto reductase(AKR1B1) and human monomeric carbonyl reductase. Since 1'-OXPH_4 has been suggested to be nonenzymatically converted into sepiapterin, in an incubation mixture containing PPH_4 and AKR1B1, sepiapterin was determined by its derivative as biopterin. No sepiapterin was detected in the incubation mixture when the mixture containing 800 pmol of 1'-OXPH_4 was further incubated at 37℃ for 2 h in darkness. This result suggests that the rate of the nonenzymatic formation of sepiapterin from 1'-OXPH_4 is quite low. The findings obtained here indicate that the proposed pathway in which a nonenzymatic conversion of 1'-OXPH_4 to sepiapterin occurs may be difficult or unlikely to proceed in humans.
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Report
(3 results)
Research Products
(10 results)
