Total Chemical Synthesis of SUMO and SUMO-Based Probes for Profiling the Activity of SUMO-Specific Proteases

Angewandte Chemie
Monique P C MulderHuib Ovaa

Abstract

SUMO is a post-translational modifier critical for cell cycle progression and genome stability that plays a role in tumorigenesis, thus rendering SUMO-specific enzymes potential pharmacological targets. However, the systematic generation of tools for the activity profiling of SUMO-specific enzymes has proven challenging. We developed a diversifiable synthetic platform for SUMO-based probes by using a direct linear synthesis method, which permits N- and C-terminal labelling to incorporate dyes and reactive warheads, respectively. In this manner, activity-based probes (ABPs) for SUMO-1, SUMO-2, and SUMO-3-specific proteases were generated and validated in cells using gel-based assays and confocal microscopy. We further expanded our toolbox with the synthesis of a K11-linked diSUMO-2 probe to study the proteolytic cleavage of SUMO chains. Together, these ABPs demonstrate the versatility and specificity of our synthetic SUMO platform for in vitro and in vivo characterization of the SUMO protease family.

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Citations

Sep 7, 2018·Angewandte Chemie·Katharina F WittingHuib Ovaa
Sep 29, 2018·Chembiochem : a European Journal of Chemical Biology·Gerbrand J van der Heden van NoortHuib Ovaa
Aug 21, 2019·Oxidative Medicine and Cellular Longevity·Xiyun BianXiaozhi Liu
May 18, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Muhammad Murtaza Hassan, Olasunkanmi O Olaoye
Jun 15, 2021·Chemical Science·Xin SuiLei Liu
Jul 31, 2019·ACS Chemical Biology·Yuqing JiaHuib Ovaa

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Methods Mentioned

BETA
ubiquitination
fluorescence microscopy
circular dichroism
confocal microscopy

Software Mentioned

SUMO ABP

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