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The novel biosynthetic pathway of tetrahydrobiopterin

四氢生物蝶呤的新型生物合成途径

基本信息

批准号：
14570776
负责人：
IINO Teruhiko
金额：
$ 2.05万
依托单位：
Ninon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

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.

四氢生物蝶呤(BH4)是芳香族氨基酸羟基酶和一氧化氮合酶的辅因子。该生物合成包括两个还原步骤，由sepiapterin还原酶催化。然而，sepiapterin还原酶缺乏症患者的尿蝶呤排泄正常，没有高苯丙氨酸血症，这表明其他酶催化了这两个还原步骤。在这项研究中，使用了几种属于醛酮还原酶(AKR)家族的人重组酶来检测四氢蝶呤中间体的还原酶活性。在AKR家族酶对PPH4的还原中，3-α-羟基类固醇脱氢酶2型生成2‘-OXPH4，醛糖还原酶、醛还原酶和20-α-羟基类固醇脱氢酶生成1’-OXPH4，3种α-羟基类固醇脱氢酶(1型和3型)分别检测到1‘-OXPH4和2’-OXPH4为主产物和次要产物。醛糖还原酶和3-α-羟基类固醇脱氢酶的活性(分别为106nmoL/mg/min和35nmoL/mg/min)高于其他酶(0.2nmoL/mg/min和4.0nmol/mg/min)。醛糖还原酶将2‘-OXPh_4还原为BH_4，而其他酶对2-OXPh_4和1’-OXPh_4均无活性。这些结果表明，四氢蝶呤中间体是人AKR家族酶的天然底物，并提出了一种从PPh_4到BH_4的新的替代途径，其中3-α-羟基类固醇脱氢酶2型和醛糖还原酶协同工作。