Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members
Tetrahydrobiopterin is synthesized from 6-pyruvoyl-tetrahydropterin by the human aldo-keto reductase AKR1 family members
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DOI：
10.1016/s0003-9861(03)00295-9
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发表时间：
2003-08-15
影响因子：
3.9
通讯作者：
Hara, A
中科院分区：
文献类型：
--
作者：
Iino, T;Tabata, M;Hara, A
四氢生物蝶呤（BH 4）是芳香族氨基酸羟化酶和一氧化氮合酶的辅因子。该生物合成包括由sepiapterin还原酶催化的两个还原步骤。中间体6-乙酰基四氢蝶呤（PPH 4）被还原为1'-氧代-2'-羟丙基-四氢蝶呤（1'-OXPH 4）或1'-羟基-2'-氧代丙基-四氢蝶呤（2'-OXPH 4），后者进一步转化为BH 4。然而，与sepiapterin还原酶缺乏症患者显示正常的尿液排泄的蝶呤没有高苯丙氨酸血症，这表明其他酶催化的两个还原步骤。在这项研究中，使用属于醛酮还原酶（AKR）家族和短链脱氢酶/还原酶（SDR）家族的几种人重组酶检测了四氢蝶呤中间体的还原酶活性。在通过AKR家族酶还原PPH 4中，2 ′-OXPH 4由2型3 α-羟基类固醇脱氢酶形成，而1 ′-OXPH 4由醛糖还原酶、醛还原酶和20 α-羟基类固醇脱氢酶产生，并且1 ′-OXPH 4和2 ′-OXPH 4均被检测为3 α-羟基类固醇脱氢酶（1型和3型）的主要和次要产物。醛糖还原酶和3 α-羟基类固醇脱氢酶2型的活性（分别为106和35 nmol/mg/min）高于其他酶的活性（0.2 - 4.0 nmol/mg/min）。在SDR家族酶中，单体羰基还原酶表现出5.0 nmol/mg/min的低1'-OXPH 4形成活性，但L-木酮糖还原酶和过氧化物酶体四聚体羰基还原酶不从PPH 4形成任何还原产物。醛糖还原酶将2'-OXPH 4还原为BH 4，但其他酶对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类AKR家族酶的天然底物，并提出了一种新的替代途径，从PPH 4到BH 4，其中3 α-羟基类固醇脱氢酶2型和醛糖还原酶协同工作。(C)2003 Elsevier Science（美国）。All rights reserved.
Tetrahydrobiopterin (BH4) is a cofactor for aromatic amino acid hydroxylases and nitric oxide synthase. The biosynthesis includes two reduction steps catalyzed by sepiapterin reductase. An intermediate, 6-pyruvoyltetrahydropterin (PPH4) is reduced to 1'-oxo-2'-hydroxypropyl-tetrahydropterin (1'-OXPH4) or 1'-hydroxy-2'-oxopropyl-tetrahydropterin (2'-OXPH4), which is further converted to BH4. 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 study, the reductase activities for the tetrahydropterin intermediates were examined using several human recombinant enzymes belonging to the aldo-keto reductase (AKR) family and short-chain dehydrogenase/reductase (SDR) family. In the reduction of PPH4 by AKR family enzymes, 2'-OXPH4 was formed by 3alpha-hydroxysteroid dehydrogenase type 2, whereas 1'-OXPH4 was produced by aldose reductase, aldehyde reductase, and 20alpha-hydroxysteroid dehydrogenase, and both 1'-OXPH4 and 2'-OXPH4 were detected as the major and minor products by 3alpha-hydroxysteroid dehydrogenases (types 1 and 3). The activities of aldose reductase and 3alpha-hydroxysteroid dehydrogenase type 2 (106 and 35 nmol/mg/min, respectively) were higher than those of the other enzymes (0.2-4.0 nmol/mg/min). Among the SDR family enzymes, monomeric carbonyl reductase exhibited low 1'-OXPH4-forming activity of 5.0 nmol/mg/min, but L-xylulose reductase and peroxisomal tetrameric carbonyl reductase did not form any reduced product from PPH4. Aldose reductase reduced 2'-OXPH4 to BH4, but the other enzymes were inactive towards both 2'-OXPH4 and 1'-OXPH4. These results indicate that the tetrahydropterin intermediates are natural substrates of the human AKR family enzymes and suggest a novel alternative pathway from PPH4 to BH4, in which 3alpha-hydroxysteroid dehydrogenase type 2 and aldose reductase work in concert. (C) 2003 Elsevier Science (USA). All rights reserved.