Characterization of type 12 17β-hydroxysteroid dehydrogenase, an isoform of type 3 17β-hydroxysteroid dehydrogenase responsible for estradiol formation in women
Characterization of type 12 17β-hydroxysteroid dehydrogenase, an isoform of type 3 17β-hydroxysteroid dehydrogenase responsible for estradiol formation in women
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DOI：
10.1210/me.2005-0058
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发表时间：
2006-02-01
影响因子：
--
通讯作者：
Labrie, F
中科院分区：
文献类型：
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作者：
Luu-The, V;Tremblay, P;Labrie, F
一种新的17β-羟基类固醇脱氢酶(17-β-HSD)，按时间顺序命名为12型17-β-HSD(17-HSD12)，将雌酮(E1)转化为雌二醇(E2)，通过与3型17-β-HSD(17-HSD3)的序列相似性被鉴定，该酶催化睾丸中雄烯二酮生成睾酮。两者都由跨越11个外显子的大基因编码，其中大多数显示出相同的大小。利用稳定表达17β-HSD12的人胚胎肾-293细胞，我们发现该酶选择性和有效地催化E1转化为E2，从而确定其在雌激素形成中的作用，而17β-HSD3参与了睾丸中雄激素睾酮的生物合成。利用实时定量聚合酶链式反应(Real-Time-PCR)定量检测了17β-HSD12和17β-HSD在人体一系列组织中的表达水平，发现17β-HSD12在卵巢和乳腺中的表达水平最高。为了更好地了解17β-HSD3和17β-HSD12底物特异性差异的结构基础，我们使用17型17β-HSD的坐标和定点突变进行了三维结构建模。结果表明，在17β-HSD12中，体积较大的氨基酸F234可能会阻止雄烯二酮的进入。总体而言，我们的结果强烈表明，17β-HSD12是主要的雌激素17β-HSD，负责将女性的E1转化为E2，特别是在卵巢中，卵巢是绝经前雌激素的主要来源。
A novel 17 beta-hydroxysteroid dehydrogenase ( 17 beta-HSD) chronologically named type 12 17 beta-HSD (17 beta-HSD12), that transforms estrone (E1) into estradiol (E2) was identified by sequence similarity with type 3 17 beta-HSD ( 17 beta-HSD3) that catalyzes the formation of testosterone from androstenedione in the testis. Both are encoded by large genes spanning 11 exons, most of them showing identical size. Using human embryonic kidney-293 cells stably expressing 17 beta-HSD12, we have found that the enzyme catalyzes selectively and efficiently the transformation of E1 into E2, thus identifying its role in estrogen formation, in contrast with 17 beta-HSD3, the enzyme involved in the biosynthesis of the androgen testosterone in the testis. Using real-time PCR to quantify mRNA in a series of human tissues, the expression levels of 17 beta-HSD12 as well as two other enzymes that perform the same transformation of E1 into E2, namely type 1 17 beta-HSD and type 7 17 beta-HSD, it was found that 17 beta-HSD12 mRNA is the most highly expressed in the ovary and mammary gland. To obtain a better understanding of the structural basis of the difference in substrate specificity between 17 beta-HSD3 and 17 beta-HSD12, we have performed tridimensional structure modelization using the coordinates of type 1 17 beta-HSD and site-directed mutagenesis. The results show the potential role of bulky amino acid F234 in 17 beta-HSD12 that blocks the entrance of androstenedione. Overall, our results strongly suggest that 17 beta-HSD12 is the major estrogenic 17 beta-HSD responsible for the conversion of E1 to E2 in women, especially in the ovary, the predominant source of estrogens before menopause.