Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception.,ACS Central Science

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Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception.
ACS Central Science ( IF 12.7 ) Pub Date : 2018-07-12 , DOI: 10.1021/acscentsci.8b00239
Samuel J Pellock ₁ , Benjamin C Creekmore ₁ , William G Walton ₁ , Naimee Mehta ₁ , Kristen A Biernat ₁ , Andrew P Cesmat ₁ , Yamuna Ariyarathna ₁ , Zachary D Dunn ₁ , Bo Li ₁ , Jian Jin ₂ , Lindsey I James ₁ , Matthew R Redinbo _{1,

1}

Affiliation

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.

中文翻译：

通过截获催化循环抑制肠道微生物β-葡萄糖醛酸苷酶。

微生物β-葡糖醛酸糖苷酶（GUSs）会导致严重的肠毒性，从而限制了癌症药物和其他治疗剂的功效。细菌GUS的选择性抑制剂已显示可减轻这些副作用。使用结构和化学生物学，质谱法和基于细胞的测定法，我们建立了含哌嗪的GUS抑制剂拦截这些保留的糖基水解酶的糖基酶催化中间体。我们证明基于哌嗪的化合物是依赖于底物的GUS抑制剂，与作为哌嗪连接的葡糖醛酸（GlcA，葡糖醛酸）的GUS-GlcA催化中间体结合。我们通过LC-MS证实了GUS依赖的抑制剂-葡萄糖醛酸苷共轭物的形成，并显示甲基化的哌嗪类似物显示出显着降低的效力。我们进一步证明，来自许多类别的一系列批准的含哌嗪和哌啶的药物，包括用于治疗抑郁症，感染和癌症的药物，均以相同的机制起作用，并且我们通过基因编辑证实了这些化合物选择性抑制GUS在活细菌细胞中。总之，这些数据揭示了GUS抑制的独特机制，并表明多种疗法可能会影响人肠道中GUS的活性。

更新日期：2018-07-12

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