Inhibition of testosterone 5 alpha-reductase by a proposed enzyme-activated, active site-directed inhibitor.
Inhibition of testosterone 5 alpha-reductase by a proposed enzyme-activated, active site-directed inhibitor.
复制标题
所提出的酶激活活性定点抑制剂对睾酮 5 α 还原酶的抑制作用。
DOI：
10.1016/0006-291x(80)90735-4
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发表时间：
1980
影响因子：
3.1
通讯作者：
G. L. Schatzman
中科院分区：
文献类型：
--
作者：
T. R. Blohm;B. Metcalf;M. Laughlin;A. Sjoerdsma;G. L. Schatzman
RMI 18，341（5α，20-R）-4-重氮-21-羟基-20-甲基异戊烯-3-酮是睾酮5α-还原酶的酶激活不可逆抑制剂。它产生了时间依赖性的，显然是一阶失活的酶，这可以拮抗底物，指示不可逆的失活发生在酶的活性位点。与传统的5α-类固醇不同，RMI 18，341对该酶有很高的亲和力：表观Ki= 3.5 × 10− 8 M。在25°C下，可逆EI复合物的形成对于酶失活不是限速的，并且这表示为抑制反应的饱和动力学。与其他3-酮-5 α-类固醇相比，RMI 18，341对大鼠前列腺的3α-羟基类固醇氧化还原酶无抑制作用。对睾酮5α-还原酶的特异性、不可逆性和高亲和力应使RMI 18，341成为阐明睾酮代谢物生理作用的有用工具。
RMI 18,341 (5α,20-R)-4-diazo-21-hydroxy-20-methylpregnan-3-one, was designed to be an enzyme-activated irreversible inhibitor of testosterone 5α-reductase. It produced time-dependent, apparently first-order inactivation of the enzyme, which can be antagonized by substrate, indicative of irreversible inactivation occurring at the enzyme active site. Unlike conventional 5α-steroids, RMI 18,341 has a high affinity for the enzyme:apparent Ki= 3.5 × 10−8M. At 25°C, formation of the reversible EI complex is not rate-limiting for enzyme inactivation, and this is expressed as saturation kinetics for the inhibition reaction. RMI 18,341 produces no inhibition of 3α-hydroxysteroid oxidoreductase of rat prostate, in contrast to other 3-keto-5α-steroids. The specificity, irreversibility and high affinity for testosterone 5α-reductase should make RMI 18,341 a useful tool in elucidation of the physiological roles of testosterone metabolites.