Paralogues of porcine aromatase cytochrome P450: A novel hydroxylase activity is associated with the survival of a duplicated gene
Paralogues of porcine aromatase cytochrome P450: A novel hydroxylase activity is associated with the survival of a duplicated gene
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DOI：
10.1210/en.2003-1595
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发表时间：
2004-05-01
期刊：
影响因子：
4.8
通讯作者：
Conley, AJ
中科院分区：
文献类型：
--
作者：
Corbin, CJ;Mapes, SM;Conley, AJ
研究了猪芳香化酶细胞色素P450（P450 arom）的性腺和胎盘旁系同源物的新催化特性，以揭示对繁殖至关重要的酶的重复拷贝的进化生存。重组性腺P450 arom催化睾酮形成一种新的代谢产物，通过气相色谱/质谱和生化分析鉴定为1 β-羟基睾酮（1 β OH-T），几乎与17 β-雌二醇（E-2）成相等比例。这种活性在与P450 arom的猪胎盘颗粒（或其他直系同源物）的反应中不存在，并且与雄烯二酮的反应最小。与猪酶以及牛和人P450 arom孵育表明，1 β OH-T不能芳香化，1 β OH-T在体外激活前列腺癌细胞的雄激素受体。猪睾丸和卵泡颗粒组织合成1 β OH-T，睾丸静脉血浆中也检测到1 β OH-T。这些结果构成了一种新的，也许是有效的，nonaromatizable睾酮的代谢产物，其合成（矛盾的）可以明确归因于猪P450 arom的性腺paradial的活动的第一个鉴定。它可能代表了与固定相关的功能的进化增益和CYP 19复制后基因的存活。新的活动和适应功能可能存在于其他重复的脊椎动物芳香化酶。
The gonadal and placental paralogues of porcine aromatase cytochrome P450 (P450arom) were examined for novel catalytic properties to shed light on the evolutionary survival of duplicated copies of an enzyme critical to reproduction. Recombinant gonadal P450arom catalyzed the formation of a novel metabolite from testosterone, identified by gas chromatography/mass spectrometry and biochemical analyses as 1beta-hydroxytestosterone (1betaOH-T), in almost equal proportion to 17beta-estradiol (E-2). This activity was absent in reactions with the porcine placental paralogue (or other orthologues) of P450arom and was minimal with androstenedione. Incubations with both porcine enzymes and with bovine and human P450arom demonstrated that 1betaOH-T was not aromatizable, and 1betaOH-T activated the androgen receptor of prostate cancer cells in vitro. Porcine testicular and follicular granulosa tissues synthesized 1betaOH-T, which was also detected in testicular venous plasma. These results constitute the first of identification of a novel, perhaps potent, nonaromatizable metabolite of testosterone, whose synthesis (paradoxically) can be definitively ascribed to the activity of the gonadal paralogue of porcine P450arom. It probably represents an evolutionary gain of function associated with fixation and the survival of the genes after CYP19 duplication. Novel activities and adaptive functions may exist among other duplicated vertebrate aromatases.