Novel activities of CYP11A1 and their potential physiological significance.
Novel activities of CYP11A1 and their potential physiological significance.
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DOI：
10.1016/j.jsbmb.2014.11.010
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发表时间：
2015-07
期刊：
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 AT;Li W;Kim TK;Semak I;Wang J;Zjawiony JK;Tuckey RC
仅在脊椎动物中发现的CYP 11 A1催化类固醇生成的第一步，其中胆固醇转化为双烯醇酮。纯化的酶还将链甾醇和植物甾醇（包括菜油甾醇和β-谷甾醇）转化为双烯醇酮。最初使用纯化酶的研究表明，7-脱氢胆固醇（7 DHC）、麦角固醇、光甾醇3和维生素D3和D2也可作为CYP 11 A1的底物，其中7 DHC更好，维生素D3和D2是比胆固醇差的底物。肾上腺、胎盘和表皮角质形成细胞也可以进行这些转化，并且在表皮、肾上腺和血清中检测到7-脱氢双烯醇酮，并且在人血清和表皮中检测到20-羟基维生素D3。因此，这种代谢似乎确实发生在体内，尽管其数量上的重要性和生理作用仍有待确定。在Smith-Lemli-Opitz综合征患者中检测到Δ 7类固醇进一步支持了CYP 11 A1在体内对7 DHC的作用。CYP 11 A1的活性受底物结构的影响，其中具有甾体或Δ7-甾体结构的甾醇在C22和C20处羟基化后发生侧链裂解。相反，维生素D的代谢涉及从C20开始的连续羟基化，但不会导致裂解。使用CYP 11 A1晶体结构的分子建模预测，胆固醇合成的其他中间体也可以作为CYP 11 A1的底物。最后，CYP 11 A1衍生的开环甾体羟基衍生物和Δ 7甾体在体外给药时具有生物活性，其方式取决于化合物的结构和靶细胞的谱系，表明这些代谢产物具有生理作用。这篇文章是题为“SI：类固醇/类固醇信号”的特刊的一部分。
CYP11A1, found only in vertebrates, catalyzes the first step of steroidogenesis where cholesterol is converted to pregnenolone. The purified enzyme, also converts desmosterol and plant sterols including campesterol and β-sitosterol, to pregnenolone. Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol. Adrenal glands, placenta, and epidermal keratinocytes can also carry out these conversions and 7-dehydropregnenolone has been detected in the epidermis, adrenal glands, and serum, and 20-hydroxyvitamin D3 was detected in human serum and the epidermis. Thus, this metabolism does appear to occur in vivo, although its quantitative importance and physiological role remain to be established. CYP11A1 action on 7DHC in vivo is further supported by detection of Δ7steroids in Smith-Lemli-Opitz syndrome patients. The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage. Molecular modeling using the crystal structure of CYP11A1 predicts that other intermediates of cholesterol synthesis could also serve as substrates for CYP11A1. Finally, CYP11A1-derived secosteroidal hydroxy-derivatives and Δ7steroids are biologically active when administered in vitro in a manner dependent on the structure of the compound and the lineage of the target cells, suggesting physiological roles for these metabolites. This article is part of a special issue entitled ‘SI: Steroid/Sterol signaling’.