Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity.
Structure and Inhibition of Microbiome β-Glucuronidases Essential to the Alleviation of Cancer Drug Toxicity.
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DOI：
10.1016/j.chembiol.2015.08.005
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发表时间：
2015-09-17
影响因子：
--
通讯作者：
Redinbo MR
中科院分区：
文献类型：
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作者：
Wallace BD;Roberts AB;Pollet RM;Ingle JD;Biernat KA;Pellock SJ;Venkatesh MK;Guthrie L;O'Neal SK;Robinson SJ;Dollinger M;Figueroa E;McShane SR;Cohen RD;Jin J;Frye SV;Zamboni WC;Pepe-Ranney C;Mani S;Kelly L;Redinbo MR
最近显示，选择性抑制细菌β-葡萄糖醛酸苷酶可减轻药物诱导的小鼠胃肠道毒性，包括广泛使用的抗癌药物伊立替康引起的损伤。在这里，我们报告了来自厚壁菌门无乳链球菌和产气荚膜梭菌和变形杆菌大肠杆菌的代表性β-葡萄糖醛酸苷酶的晶体结构，以及来自脆弱拟杆菌的β-葡萄糖醛酸苷酶的表征。虽然在结构上很大程度上相似，但这些酶在催化特性和抑制倾向方面表现出显着差异，表明微生物组保持了邻苯二甲酸酶的功能多样性。设计的抑制剂结构的微小变化可诱导β-葡萄糖醛酸酶活性位点的显著构象变化。最后，我们确定β-葡萄糖醛酸酶抑制不会改变伊立替康或其代谢产物在小鼠中的血清药代动力学。总之，这些数据推进了我们对微生物β-葡萄糖醛酸苷酶的体外和体内理解，这是一组有希望的控制药物诱导胃肠道毒性的新靶点。
The selective inhibition of bacterial β-glucuronidases was recently shown to alleviate drug-induced gastrointestinal toxicity in mice, including the damage caused by the widely used anticancer drug irinotecan. Here, we report crystal structures of representative β-glucuronidases from the Firmicutes Streptococcus agalactiae and Clostridium perfringens and the Proteobacterium Escherichia coli, and the characterization of a β-glucuronidase from the Bacteroidetes Bacteroides fragilis. While largely similar in structure, these enzymes exhibit marked differences in catalytic properties and propensities for inhibition, indicating that the microbiome maintains functional diversity in orthologous enzymes. Small changes in the structure of designed inhibitors can induce significant conformational changes in the β-glucuronidase active site. Finally, we establish that β-glucuronidase inhibition does not alter the serum pharmacokinetics of irinotecan or its metabolites in mice. Together, the data presented advance our in vitro and in vivo understanding of the microbial β-glucuronidases, a promising new set of targets for controlling drug-induced gastrointestinal toxicity.