Inhibition of Human Steroid 5β-Reductase (AKR1D1) by Finasteride and Structure of the Enzyme-Inhibitor Complex
Inhibition of Human Steroid 5β-Reductase (AKR1D1) by Finasteride and Structure of the Enzyme-Inhibitor Complex
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DOI：
10.1074/jbc.c109.016931
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发表时间：
2009-07-24
影响因子：
4.8
通讯作者：
Christianson, David W.
中科院分区：
文献类型：
--
作者：
Drury, Jason E.;Di Costanzo, Luigi;Christianson, David W.
δ（4）-3-酮类固醇功能存在于除雌激素外的几乎所有类固醇激素中。A环功能化的第一步在人体中由类固醇5 α-或5 β-还原酶介导。芬达是一种具有亚纳摩尔亲和力的5 α-还原酶2型的基于机制的灭活剂，广泛用作治疗良性前列腺增生的治疗剂。它也用于雄激素依赖性前列腺癌的雄激素剥夺，并已被检查为前列腺癌的化学预防剂。芬那肽对类固醇5 β-还原酶（AKR 1D 1）的影响此前尚未报道。我们发现，芬那肽竞争性抑制AKR 1D 1与低微摩尔亲和力，但不作为一个机制为基础的灭活剂。在1.7埃分辨率下测定的AKR1D1.NADP（+）.非那肽复合物的结构表明，NADPH不可能还原非那肽的δ（1-2）-烯，因为辅因子和类固醇彼此不邻近。非那肽的C3-酮接受来自AKR 1D 1活性位点中催化残基Tyr-58和Glu-120的氢键，为观察到的竞争性抑制提供了解释。这是首次报道的与参与类固醇激素代谢的酶结合的非那肽结构。
The Delta(4)-3-ketosteroid functionality is present in nearly all steroid hormones apart from estrogens. The first step in functionalization of the A-ring is mediated in humans by steroid 5 alpha- or 5 beta-reductase. Finasteride is a mechanism-based inactivator of 5 alpha-reductase type 2 with subnanomolar affinity and is widely used as a therapeutic for the treatment of benign prostatic hyperplasia. It is also used for androgen deprivation in hormone-dependent prostate carcinoma, and it has been examined as a chemopreventive agent in prostate cancer. The effect of finasteride on steroid 5 beta-reductase (AKR1D1) has not been previously reported. We show that finasteride competitively inhibits AKR1D1 with low micromolar affinity but does not act as a mechanism-based inactivator. The structure of the AKR1D1.NADP(+).finasteride complex determined at 1.7 angstrom resolution shows that it is not possible for NADPH to reduce the Delta(1-2)-ene of finasteride because the cofactor and steroid are not proximal to each other. The C3-ketone of finasteride accepts hydrogen bonds from the catalytic residues Tyr-58 and Glu-120 in the active site of AKR1D1, providing an explanation for the competitive inhibition observed. This is the first reported structure of finasteride bound to an enzyme involved in steroid hormone metabolism.