The Crystal Structure of Mouse Ces2c, a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1

Abstract

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.

Evaluation of Drug-Drug Interactions via Inhibition of Hydrolases by Orlistat, an Anti-Obesity Drug

“…5A and B). Mouse Ces2c is recognized as an ortholog of human CES2 (Eisner et al, 2022), but amino acid homology is not as high (71%), and whether Ces2c catalyzes acebutolol needs to be examined using the expression system. Although rat Ces2 is not expressed in the liver (Taketani et al, 2007;Satoh and Hosokawa, 2010), acebutolol hydrolase activity in rat liver microsomes was higher than that in intestinal microsomes (Table 2; Fig.…”

Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

“…Given the rapid conversion into NHC and NHC-TP, Molnupiravir is barely detected in all tissues, however, NHC and NHC-TP are observed in all tissues, primarily in the lungs and spleen, in a dose-dependent manner 63 . Molnupiravir is hydrolyzed to NHC by CES, especially CES2 64 , 65 . NHC is converted into NHC-TP by host kinases and phosphatases in cells 63 .…”

“…Therefore, the plasma concentration of NHC may be decreased when TCM is combined with Molnupiravir. On the other hand, neither Molnupiravir nor NHC functioned as substrates/inhibitor/inducer of any important transporters and enzymes that mediate drug–drug interactions 63 , 65 . Thus, the effect of Molnupiravir on the six TCM recipes through a pharmacokinetic mechanism via drug metabolizing enzymes and transporters may not occur.…”