Enzymatic metabolism of ergosterol by cytochrome P450scc to biologically active 17α,24-dihydroxyergosterol
Enzymatic metabolism of ergosterol by cytochrome P450scc to biologically active 17α,24-dihydroxyergosterol
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DOI：
10.1016/j.chembiol.2005.06.010
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发表时间：
2005-08-01
影响因子：
--
通讯作者：
Tuckey, RC
中科院分区：
文献类型：
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作者：
Slominski, A;Semak, I;Tuckey, RC
我们证明了细胞色素P450scc在重组系统或分离的肾上腺线粒体中代谢麦角甾醇。主要反应产物为17 α，24-二羟基麦角甾醇。纯化后的P450scc还产生了羟基麦角甾醇作为次要产物，它可能是合成17 α，24-二羟基麦角甾醇的中间体。与胆固醇和7-脱氢胆固醇相比，麦角甾醇侧链没有断裂。核磁共振分析清楚地定位了C24的一个羟基，有证据表明第二个羟基在C17.17 α，24-二羟基麦角甾醇抑制HaCaT角质形成细胞和黑色素瘤细胞的增殖。因此，与胆固醇和7-脱氢胆固醇相比，麦角甾醇的24-甲基和C22- c23双键阻止了P450scc对侧链的切割，使酶的羟化酶活性从C22和C20变为C24和C17，产生生物活性产物。
We demonstrate the metabolism of ergosterol by cytochrome P450scc in either a reconstituted system or isolated adrenal mitochondria. The major reaction product was identified as 17 alpha,24-dihydroxyergosterol. Purified P450scc also generated hydroxyergosterol as a minor product, which is probably an intermediate in the synthesis of 17 alpha,24-dihydroxyergosterol. In contrast to cholesterol and 7-dehydrocholesterol, cleavage of the ergosterol side chain was not observed. NMR analysis clearly located one hydroxyl group to C24, with evidence that the second hydroxyl group is at C17.17 alpha,24-Dihydroxyergosterol inhibited cell proliferation of HaCaT keratinocytes and melanoma cells. Thus, in comparison with cholesterol and 7-dehydrocholesterol, the 24-methyl group and the C22-C23 double bond of ergosterol prevent side chain cleavage by P450scc and change the enzyme's hydroxylase activity from C22 and C20, to C24 and C17, generating bioactive product.