Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception.
Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception.
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DOI：
10.1021/acscentsci.8b00239
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发表时间：
2018-07-25
影响因子：
18.2
通讯作者：
Redinbo MR
中科院分区：
文献类型：
--
作者：
Pellock SJ;Creekmore BC;Walton WG;Mehta N;Biernat KA;Cesmat AP;Ariyarathna Y;Dunn ZD;Li B;Jin J;James LI;Redinbo MR
微生物β-葡萄糖醛酸苷酶（GUS）会导致严重的肠道毒性，限制癌症药物和其他治疗药物的疗效。细菌GUS的选择性抑制剂已被证明可以减轻这些副作用。使用结构和化学生物学，质谱，和基于细胞的测定，我们建立哌嗪含GUS抑制剂拦截这些保留糖基水解酶的糖基酶催化中间体。我们证明，哌嗪为基础的化合物是底物依赖性的GUS抑制剂，结合GUS-GlcA催化中间体作为哌嗪连接的葡萄糖醛酸苷（GlcA，葡萄糖醛酸）。我们通过LC-MS证实了GUS依赖性的葡萄糖醛酸苷结合物的形成，并表明甲基化哌嗪类似物显示出显著降低的效力。我们进一步证明了一系列批准的含哌嗪和哌啶的药物，包括治疗抑郁症，感染和癌症的药物，通过相同的机制发挥作用，并且我们通过基因编辑证实这些化合物选择性地抑制活细菌细胞中的GUS。总之，这些数据揭示了GUS抑制的独特机制，并表明一系列治疗剂可能影响人肠道中的GUS活性。含哌嗪的化合物是细菌β-葡萄糖醛酸苷酶的底物依赖性抑制剂，其拦截葡萄糖醛酸连接的催化中间体。
Microbial β-glucuronidases (GUSs) cause severe gut toxicities that limit the efficacy of cancer drugs and other therapeutics. Selective inhibitors of bacterial GUS have been shown to alleviate these side effects. Using structural and chemical biology, mass spectrometry, and cell-based assays, we establish that piperazine-containing GUS inhibitors intercept the glycosyl-enzyme catalytic intermediate of these retaining glycosyl hydrolases. We demonstrate that piperazine-based compounds are substrate-dependent GUS inhibitors that bind to the GUS–GlcA catalytic intermediate as a piperazine-linked glucuronide (GlcA, glucuronic acid). We confirm the GUS-dependent formation of inhibitor–glucuronide conjugates by LC–MS and show that methylated piperazine analogs display significantly reduced potencies. We further demonstrate that a range of approved piperazine- and piperidine-containing drugs from many classes, including those for the treatment of depression, infection, and cancer, function by the same mechanism, and we confirm through gene editing that these compounds selectively inhibit GUS in living bacterial cells. Together, these data reveal a unique mechanism of GUS inhibition and show that a range of therapeutics may impact GUS activities in the human gut. Piperazine-containing compounds are substrate-dependent inhibitors of bacterial β-glucuronidases that intercept the glucuronic-acid-linked catalytic intermediate.
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DOI：
10.1016/j.str.2017.05.003
发表时间：
2017-07-05
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Pollet RM;D'Agostino EH;Walton WG;Xu Y;Little MS;Biernat KA;Pellock SJ;Patterson LM;Creekmore BC;Isenberg HN;Bahethi RR;Bhatt AP;Liu J;Gharaibeh RZ;Redinbo MR
通讯作者：
Redinbo MR
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.6
作者：
Roberts, Adam B.;Wallace, Bret D.;Redinbo, Matthew R.
通讯作者：
Redinbo, Matthew R.
影响因子：
5.1
作者：
SLY, WS;QUINTON, BA;RIMOIN, DL
通讯作者：
RIMOIN, DL
影响因子：
51.1
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.