Structural basis for the selective inhibition of human 3beta-hydroxysteroid dehydrogenase 1 in human breast tumor MCF-7 cells.
Structural basis for the selective inhibition of human 3beta-hydroxysteroid dehydrogenase 1 in human breast tumor MCF-7 cells.
复制标题
DOI：
10.1016/j.mce.2008.09.029
复制
发表时间：
2009-03-25
影响因子：
4.1
通讯作者：
Kacsoh B
中科院分区：
文献类型：
--
作者：
Thomas JL;Bucholtz KM;Sun J;Mack VL;Kacsoh B
Human 3β-hydroxysteroid dehydrogenase/isomerase type 1 (3β-HSD1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors and may be a target enzyme for inhibition in the treatment of breast cancer in postmenopausal women. Human 3β-HSD2 participates in the production of cortisol and aldosterone in the human adrenal gland in this population. In our recombinant human breast tumor MCF-7 Tet-off cells that express either 3β-HSD1 or 3β-HSD2, trilostane and epostane inhibit the DHEA-induced proliferation of MCF-7 3β-HSD1 cells with 12-to 16- fold lower IC50 values compared to the MCF-7 3β-HSD2 cells. The compounds also competitively inhibit purified human 3β-HSD1 with 12- to 16-fold lower Ki values compared to the noncompetitive Ki values measured for human 3β-HSD2. Using our structural model of 3β-HSD1, trilostane or 17β-acetoxy-trilostane was docked in the active site of 3β-HSD1, and Arg195 in 3β-HSD1 or Pro195 in 3β-HSD2 was identified as a potentially critical residue (one of 23 nonidentical residues in the two isoenzymes). The P195R mutant of 3β-HSD2 were created, expressed and purified. Kinetic analyses of enzyme inhibition suggest that the high-affinity, competitive inhibition of 3β-HSD1 by trilostane and epostane may be related to the presence of Arg195 in 3β-HSD1 vs Pro195 in 3β-HSD2.
登录
查看更多内容
影响因子：
6.1
作者：
Havelock, JC;Rainey, WE;Carr, BR
通讯作者：
Carr, BR
影响因子：
4.8
作者：
Thomas, JL;Mason, JI;Norris, W
通讯作者：
Norris, W
影响因子：
--
作者：
Gingras, S;Moriggl, R;Simard, J
通讯作者：
Simard, J
影响因子：
2.9
作者：
Thoden, JB;Frey, PA;Holden, HM
通讯作者：
Holden, HM
影响因子：
2.9
作者：
BRADFORD, MM
通讯作者：
BRADFORD, MM