Finding the mechanism of esterase D activation by a small molecule

Xinpeng Chen; Yuejun Yang; Le Su; Xiaoling Cui; Jing Shao; Shuyan Liu; Baoxiang Zhao; Junying Miao

doi:10.1016/j.bmcl.2020.127150

Finding the mechanism of esterase D activation by a small molecule

Bioorg Med Chem Lett. 2020 Jun 1;30(11):127150. doi: 10.1016/j.bmcl.2020.127150. Epub 2020 Mar 29.

Authors

Xinpeng Chen¹, Yuejun Yang², Le Su², Xiaoling Cui², Jing Shao², Shuyan Liu², Baoxiang Zhao³, Junying Miao⁴

Affiliations

¹ Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao 266237, PR China; Hubei Key Laboratory of Edible Wild Plants Conservation & Utilization, National Demonstration Center for Experimental Biology Education, School of Life Science, Hubei Normal University, Huangshi 435002, PR China.
² Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao 266237, PR China.
³ Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China.
⁴ Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Qingdao 266237, PR China; The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan 250012, PR China. Electronic address: miaojy@sdu.edu.cn.

PMID: 32247735
DOI: 10.1016/j.bmcl.2020.127150

Abstract

People with reduced esterase D (ESD) activity are susceptible to many diseases. However, how to activate ESD is still unknown. To address the question, we identified that 4-chloro-2-(5-phenyl-1-(pyridin-2-yl)-4, 5-dihydro-1H-pyrazol-3-yl) phenol (FPD5) could be a good candidate activator for ESD activity. We found that FPD5 could increase ESD activity in a dose-dependent way. FPD5 bound directly to ESD at Lys180 rather than its ubiquitination site Lys213. Site-directed mutagenesis at the binding site or the ubiquitination site inhibited FPD5 action. FPD5 increased the level of ESD mono-ubiquitination and mutESD K213A completely inhibited this action. Our findings highlighted the activation mechanism of ESD via promoting the mono-ubiquitination of ESD.

Keywords: ESD activation; FPD5; Mono-ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
HEK293 Cells
Humans
Microscopy, Confocal
Molecular Docking Simulation
Mutagenesis, Site-Directed
Pyrazoles / chemistry
Small Molecule Libraries / chemistry*
Small Molecule Libraries / metabolism
Thiolester Hydrolases / chemistry
Thiolester Hydrolases / genetics
Thiolester Hydrolases / metabolism*
Ubiquitination

Substances

Pyrazoles
Small Molecule Libraries
pyrazole
Thiolester Hydrolases
s-formylglutathione hydrolase