Abe I, Zheng Y F, Prestwich G D
Department of Medicinal Chemistry, The University of Utah, Salt Lake City 84112-5820, USA.
Biochemistry. 1998 Apr 28;37(17):5779-84. doi: 10.1021/bi980366c.
A new orally active oxidosqualene:lanosterol cyclase (OSLC) inhibitor (Ro48-8071; Morand, O. H. et al. (1997) J. Lipid Res. 38, 373-390) showed potent noncompetitive inhibition of bacterial squalene:hopene cyclase (SHC) from Alicyclobacillus acidocaldarius (IC50 = 9.0 nM, KI = 6.6 nM) and OSLC (IC50 = 40 nM, KI = 22 nM for homogeneous rat liver OSLC). A tritium-labeled isotopomer (18.8 Ci/mmol) of this nonterpenoid inhibitor, which possesses a benzophenone (BP) photophore, was chemically synthesized as a photoaffinity label. Specific, efficient covalent modification of both OSLC and SHC enzymes was observed after UV irradiation at 360 nm. Labeling of both OSLC and SHC by [3H]Ro48-8071 was competitively displaced by coincubation with a 1000-fold molar excess of 18-thia-2, 3-oxidosqualene or the nonterpenoid inhibitor BIBX79. Displacement of labeling of OSLC was also achieved with the suicide substrate (3S)-29-methylidene-2,3-oxidosqualene. Thus, the nonsubstrate Ro48-8071 and both terpenoid and nonterpenoid inhibitors of these enzymes appear to share a common binding site.
羊毛甾醇环化酶（OSLC）抑制剂（Ro48 - 8071；莫兰德，O. H. 等人（1997年）《脂质研究杂志》38卷，373 - 390页）对嗜酸 Alicyclobacillus acidocaldarius 的细菌鲨烯：藿烯环化酶（SHC）表现出强效非竞争性抑制作用（IC50 = 9.0 nM，KI = 6.6 nM）以及对 OSLC 的抑制作用（对于均一化大鼠肝脏 OSLC，IC50 = 40 nM，KI = 22 nM）。这种具有二苯甲酮（BP）光基团的非萜类抑制剂的氚标记同位素异构体（18.8 Ci/mmol）被化学合成作为光亲和标记物。在360 nm紫外线照射后，观察到 OSLC 和 SHC 酶都发生了特异性、高效的共价修饰。通过与1000倍摩尔过量的18 - 硫杂 - 2,3 - 氧化角鲨烯或非萜类抑制剂BIBX79共同孵育，[3H]Ro48 - 8071对 OSLC 和 SHC 的标记被竞争性取代。用自杀底物（3S）-29 - 亚甲基 - 2,3 - 氧化角鲨烯也实现了对 OSLC 标记的取代。因此，非底物 Ro48 - 8071 以及这些酶的萜类和非萜类抑制剂似乎共享一个共同的结合位点。
