Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles.
Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles.
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DOI：
10.1038/s42004-023-00994-3
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发表时间：
2023-09-02
影响因子：
5.9
通讯作者：
Pochapsky, Thomas C.
中科院分区：
文献类型：
--
作者：
Richard, Alaina M.;Wong, Nathan R.;Harris, Kurt;Sundar, Reethy;Scott, Emily E.;Pochapsky, Thomas C.
烷基异腈，R-NC，以前已被证明连接血红素（血红素）铁的细胞色素P450在两个可访问的氧化态（亚铁，Fe 2+，和三价铁，Fe 3+）。本文描述了四种类固醇衍生的异腈的制备及其与几种P450的相互作用，包括类固醇生成CYP 17 A1和CYP 106 A2，以及更混杂的药物代谢物CYP 3A 4和CYP 2D 6。结果发现，对于给定的P450，通过异腈官能团成功地连接血红素铁取决于类固醇骨架上异腈的位置和立体化学。光谱研究表明，异腈连接的铁血红素是稳定的还原后的亚铁形式，与再氧化产生的原始复合物。CYP 17 A1与来自孕烷酮的异腈的晶体结构进一步证实了相互作用，并确定了结合物质的绝对立体化学。细胞色素P450（CYP）酶的抑制是许多治疗方法的核心，然而，实现跨CYP酶的选择性仍然具有挑战性。在这里，作者开发了携带异腈的类固醇作为选择性类固醇生成血红素铁配体。
Alkyl isonitriles, R—NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe2+, and ferric, Fe3+). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the steroidogenic CYP17A1 and CYP106A2, as well as the more promiscuous drug metabolizers CYP3A4 and CYP2D6, is described. It was found that successful ligation of the heme iron by the isonitrile functionality for a given P450 depends on both the position and stereochemistry of the isonitrile on the steroid skeleton. Spectral studies indicate that isonitrile ligation of the ferric heme is stable upon reduction to the ferrous form, with reoxidation resulting in the original complex. A crystallographic structure of CYP17A1 with an isonitrile derived from pregnanalone further confirmed the interaction and identified the absolute stereochemistry of the bound species. The inhibition of cytochrome P450 (CYP) enzymes is central to many therapeutics, however, achieving selectivity across CYP enzymes remains challenging. Here, the authors develop isonitrile-harboring steroids as selective steroidogenic CYP heme iron ligands.
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DOI：
10.1038/s41578-020-00269-6
发表时间：
2021-04
期刊：
Nature reviews. Materials
影响因子：
--
作者：
Manzari MT;Shamay Y;Kiguchi H;Rosen N;Scaltriti M;Heller DA
通讯作者：
Heller DA
DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
2
作者：
Niwa, T;Shiraga, T;Takagi, A
通讯作者：
Takagi, A
影响因子：
3.9
作者：
Godamudunage, Malika P.;Grech, Anne M.;Scott, Emily E.
通讯作者：
Scott, Emily E.
影响因子：
2.9
作者：
Roberts, Arthur G.;Yang, Jing;Halpert, James R.;Nelson, Sidney D.;Thummel, Kenneth T.;Atkins, William M.
通讯作者：
Atkins, William M.