Oxidative 3α-hydroxysteroid dehydrogenase activity of human type 10 17β-hydroxysteroid dehydrogenase
Oxidative 3α-hydroxysteroid dehydrogenase activity of human type 10 17β-hydroxysteroid dehydrogenase
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DOI：
10.1016/j.jsbmb.2003.07.007
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发表时间：
2003-11-01
影响因子：
4.1
通讯作者：
Yang, SY
中科院分区：
文献类型：
--
作者：
He, XY;Yang, YZ;Yang, SY
体外酶试验已经证明，人10型17 β-羟基类固醇脱氢酶（17 β-HSD 10）催化5 α-雄甾烷-3 α，17 β-二醇（diol）（一种几乎无活性的雄激素）氧化为双氢睾酮（DHT），而不是雄甾酮或雄甾烷二酮。为了进一步研究这种类固醇代谢酶在完整细胞中的作用，我们在人胚肾（HEK）293细胞中产生了表达17 β-HSD 10或其无催化活性的Y168 F突变体的稳定转染子。发现如果将二醇添加到培养基中，表达17 β-HSD 10但不表达其催化失活突变体的HEK 293细胞中的DHT水平将显著增加。此外，某些恶性前列腺上皮细胞具有比正常对照更多的17 β-HSD 10，并且可以从diol产生最有效的雄激素DHT。这一事件可能会促进前列腺癌的生长。对17 β-HSD 10序列的分析表明，这种酶不具有任何ER保留信号或跨膜片段，并且不是起源于视黄醇脱氢酶的分歧。数据表明，这种HSD的独特线粒体位置[Eur. J.Biochem.268（2001）4899]不能阻止其氧化活细胞中C19甾醇的3 α-羟基。实验结果得出结论，线粒体17 β-HSD 10与微粒体视黄醇脱氢酶一起沿着在非经典雄激素合成途径中起重要作用。(C)2003 Elsevier Ltd.保留所有权利。
In vitro enzyme assays have demonstrated that human type 10 17beta-hydroxysteroid dehydrogenase(17beta-HSD10) catalyzes the oxidation of 5alpha-androstane-3alpha,17beta-diol (adiol), an almost inactive androgen, to dihydrotestosterone (DHT) rather than androsterone or androstanedione. To further investigate the role of this steroid-metabolizing enzyme in intact cells, we produced stable transfectants expressing 17beta-HSD10 or its catalytically inactive Y168F mutant in human embryonic kidney (HEK) 293 cells. It was found that DHT levels in HEK 293 cells expressing 17beta-HSD10, but not its catalytically inactive mutant, will dramatically increase if adiol is added to culture media. Moreover, certain malignant prostatic epithelial cells have more 17beta-HSD10 than normal controls, and can generate DHT, the most potent androgen, from adiol. This event might promote prostate cancer growth. Analysis of the 17beta-HSD10 sequence shows that this enzyme does not have any ER retention signal or transmembrane segments and has not originated by divergence from a retinol dehydrogenase. The data suggest that the unique mitochondrial location of this HSD [Eur. J. Biochem. 268 (2001) 4899] does not prevent it from oxidizing the 3alpha-hydroxyl group of a C19 sterol in living cells. The experimental results lead to the conclusion that mitochondrial 17beta-HSD10 plays a significant part in a non-classical androgen synthesis pathway along with microsomal retinol dehydrogenases. (C) 2003 Elsevier Ltd. All rights reserved.