Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria.
Int J Mol Sci. 2022 Oct 28;23(21):13101. doi: 10.3390/ijms232113101.
Members of the carboxylesterase 2 (Ces2/CES2) family have been studied intensively with respect to their hydrolytic function on (pro)drugs, whereas their physiological role in lipid and energy metabolism has been realized only within the last few years. Humans have one CES2 gene which is highly expressed in liver, intestine, and kidney. Interestingly, eight homologous Ces2 (Ces2a to Ces2h) genes exist in mice and the individual roles of the corresponding proteins are incompletely understood. Mouse Ces2c (mCes2c) is suggested as potential ortholog of human CES2. Therefore, we aimed at its structural and biophysical characterization. Here, we present the first crystal structure of mCes2c to 2.12 Å resolution. The overall structure of mCes2c resembles that of the human CES1 (hCES1). The core domain adopts an α/β hydrolase-fold with S230, E347, and H459 forming a catalytic triad. Access to the active site is restricted by the cap, the flexible lid, and the regulatory domain. The conserved gate (M417) and switch (F418) residues might have a function in product release similar as suggested for hCES1. Biophysical characterization confirms that mCes2c is a monomer in solution. Thus, this study broadens our understanding of the mammalian carboxylesterase family and assists in delineating the similarities and differences of the different family members.
羧酯酶 2（Ces2/CES2）家族的成员在（前）药物的水解功能方面受到了深入研究，而其在脂质和能量代谢中的生理作用仅在近几年才被认识到。人类有一个 CES2 基因，该基因在肝脏、肠道和肾脏中高度表达。有趣的是，老鼠中有 8 个同源的 Ces2（Ces2a 到 Ces2h）基因，其相应蛋白的个别作用尚不完全清楚。小鼠 Ces2c（mCes2c）被认为是人类 CES2 的潜在同源物。因此，我们旨在对其进行结构和生物物理特性的表征。在这里，我们呈现了 mCes2c 的首个晶体结构，分辨率达到 2.12 Å。mCes2c 的整体结构类似于人类 CES1（hCES1）。核心结构采用α/β水解酶折叠，S230、E347 和 H459 形成一个催化三联体。活性位点的进入受到帽、柔性盖和调节域的限制。保守的门（M417）和开关（F418）残基可能在产物释放中具有类似的功能，这与 hCES1 中的建议类似。生物物理特性的表征证实 mCes2c 在溶液中是单体。因此，这项研究拓宽了我们对哺乳动物羧酯酶家族的理解，并有助于描绘不同家族成员之间的相似性和差异。
