School of Life Science, University of Science and Technology of China, Anhui, 230026, China; Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.
Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan.
Biochem Biophys Res Commun. 2020 Jun 30;527(3):799-804. doi: 10.1016/j.bbrc.2020.04.116. Epub 2020 May 16.
When administrated orally, the vasodilating drug diltiazem can be metabolized into diacetyl diltiazem in the presence of Bacteroides thetaiotaomicron, a human gut microbe. The removal of acetyl group from the parent drug is carried out by the GDSL/SGNH-family hydrolase BT4096. Here the crystal structure of the enzyme was solved by mercury soaking and single-wavelength anomalous diffraction. The protein folds into two parts. The N-terminal part comprises the catalytic domain which is similar to other GDSL/SGNH hydrolases. The flanking C-terminal part is made up of a β-barrel subdomain and an α-helical subdomain. Structural comparison shows that the catalytic domain is most akin to acetyl-xylooligosaccharide esterase and allows a plausible binding mode of diltiazem to be proposed. The β-barrel subdomain is similar in topology to the immunoglobulin-like domains, including some carbohydrate-binding modules, of various bacterial glycoside hydrolases. Consequently, BT4096 might originally function as an oligosaccharide deacetylase with additional subdomains that could enhance substrate binding, and it acts on diltiazem just by accident.
当口服给予时，血管扩张药物地尔硫卓在人类肠道微生物拟杆菌的存在下可以代谢为二乙酰地尔硫卓。亲代药物的乙酰基的去除是由 GDSL/SGNH 家族水解酶 BT4096 完成的。在这里，通过汞浸泡和单波长异常衍射法解决了该酶的晶体结构。该蛋白质折叠成两部分。N 端部分包含催化结构域，与其他 GDSL/SGNH 水解酶相似。侧翼的 C 端部分由一个β桶亚结构域和一个α螺旋亚结构域组成。结构比较表明，催化结构域与乙酰基-木二糖酯酶最相似，并允许提出地尔硫卓的合理结合模式。β桶亚结构域在拓扑结构上与免疫球蛋白样结构域相似，包括各种细菌糖苷水解酶的一些糖结合模块。因此，BT4096 最初可能作为一种寡糖脱乙酰酶发挥作用，具有额外的亚结构域，可以增强底物结合，并且它只是偶然对地尔硫卓起作用。
