β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut.
β-Glucuronidases of opportunistic bacteria are the major contributors to xenobiotic-induced toxicity in the gut.
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DOI：
10.1038/s41598-018-34678-z
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发表时间：
2018-11-06
影响因子：
4.6
通讯作者：
Lin CH
中科院分区：
文献类型：
--
作者：
Dashnyam P;Mudududdla R;Hsieh TJ;Lin TC;Lin HY;Chen PY;Hsu CY;Lin CH
肠道细菌β-D-葡萄糖醛酸苷酶（GUS）催化从肝脏产生的β-D-葡萄糖醛酸苷中去除葡萄糖醛酸。当这些反应逆转异生物质代谢时，可能产生有害后果。人类肠道含有数百个具有可变序列和结构的GUS。为了了解任何特定细菌GUS如何促进全局GUS活性并影响人类健康，必须知道个体底物偏好。在此，我们报告了代表性GUS从其各自的葡萄糖醛酸苷产生各种外源性物质的能力各不相同。为了试图解释不同的底物偏好，我们解决了与香豆素-3-β-D-葡萄糖醛酸苷复合的细菌GUS的结构。将该结构与其他GUS结构进行比较，确定了环3（或α2-螺旋环）和环5在糖苷配基结合位点的差异，其中它们的构象、疏水性和柔性的差异似乎是GUS独特底物偏好的基础。另外的序列、结构和功能分析表明，存在几组功能相关的肠道细菌GUS。我们的研究结果指出机会性肠道细菌GUS是引起外源性毒性的细菌。我们提出了一个构效关系，应该允许预测的功能作用的GUS和选择性抑制剂的设计。
Gut bacterial β-D-glucuronidases (GUSs) catalyze the removal of glucuronic acid from liver-produced β-D-glucuronides. These reactions can have deleterious consequences when they reverse xenobiotic metabolism. The human gut contains hundreds of GUSs of variable sequences and structures. To understand how any particular bacterial GUS(s) contributes to global GUS activity and affects human health, the individual substrate preference(s) must be known. Herein, we report that representative GUSs vary in their ability to produce various xenobiotics from their respective glucuronides. To attempt to explain the distinct substrate preference, we solved the structure of a bacterial GUS complexed with coumarin-3-β-D-glucuronide. Comparisons of this structure with other GUS structures identified differences in loop 3 (or the α2-helix loop) and loop 5 at the aglycone-binding site, where differences in their conformations, hydrophobicities and flexibilities appear to underlie the distinct substrate preference(s) of the GUSs. Additional sequence, structural and functional analysis indicated that several groups of functionally related gut bacterial GUSs exist. Our results pinpoint opportunistic gut bacterial GUSs as those that cause xenobiotic-induced toxicity. We propose a structure-activity relationship that should allow both the prediction of the functional roles of GUSs and the design of selective inhibitors.
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影响因子：
16.8
作者：
Bhabha, Gira;Ekiert, Damian C.;Jennewein, Madeleine;Zmasek, Christian M.;Tuttle, Lisa M.;Kroon, Gerard;Dyson, H. Jane;Godzik, Adam;Wilson, Ian A.;Wright, Peter E.
通讯作者：
Wright, Peter E.
影响因子：
3.7
作者：
Lin XB;Dieleman LA;Ketabi A;Bibova I;Sawyer MB;Xue H;Field CJ;Baracos VE;Gänzle MG
通讯作者：
Gänzle MG
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：
6.7
作者：
Kim, DH;Jin, YH
通讯作者：
Jin, YH
影响因子：
4.4
作者：
Mountzouris, K. C.;Tsirtsikos, P.;Fegeros, K.
通讯作者：
Fegeros, K.