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Article

Intracellular Hydrolysis of Small-Molecule O-Linked N-Acetylglucosamine Transferase Inhibitors Differs among Cells and Is Not Required for Its Inhibition

1
Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia
2
Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 80082, NL-3508 TB Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editor: László Somsák
Molecules 2020, 25(15), 3381; https://doi.org/10.3390/molecules25153381
Received: 26 May 2020 / Revised: 22 July 2020 / Accepted: 24 July 2020 / Published: 25 July 2020
(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)
O-GlcNAcylation is an essential post-translational modification that occurs on nuclear and cytoplasmic proteins, regulating their function in response to cellular stress and altered nutrient availability. O-GlcNAc transferase (OGT) is the enzyme that catalyzes this reaction and represents a potential therapeutic target, whose biological role is still not fully understood. To support this research field, a series of cell-permeable, low-nanomolar OGT inhibitors were recently reported. In this study, we resynthesized the most potent OGT inhibitor of the library, OSMI-4, and we used it to investigate OGT inhibition in different human cell lines. The compound features an ethyl ester moiety that is supposed to be cleaved by carboxylesterases to generate its active metabolite. Our LC-HRMS analysis of the cell lysates shows that this is not always the case and that, even in the cell lines where hydrolysis does not occur, OGT activity is inhibited. View Full-Text
Keywords: ester hydrolysis; inhibitor; O-GlcNAc transferase; OGT inhibitor ester hydrolysis; inhibitor; O-GlcNAc transferase; OGT inhibitor
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MDPI and ACS Style

Loi, E.M.; Weiss, M.; Pajk, S.; Gobec, M.; Tomašič, T.; Pieters, R.J.; Anderluh, M. Intracellular Hydrolysis of Small-Molecule O-Linked N-Acetylglucosamine Transferase Inhibitors Differs among Cells and Is Not Required for Its Inhibition. Molecules 2020, 25, 3381. https://doi.org/10.3390/molecules25153381

AMA Style

Loi EM, Weiss M, Pajk S, Gobec M, Tomašič T, Pieters RJ, Anderluh M. Intracellular Hydrolysis of Small-Molecule O-Linked N-Acetylglucosamine Transferase Inhibitors Differs among Cells and Is Not Required for Its Inhibition. Molecules. 2020; 25(15):3381. https://doi.org/10.3390/molecules25153381

Chicago/Turabian Style

Loi, Elena M., Matjaž Weiss, Stane Pajk, Martina Gobec, Tihomir Tomašič, Roland J. Pieters, and Marko Anderluh. 2020. "Intracellular Hydrolysis of Small-Molecule O-Linked N-Acetylglucosamine Transferase Inhibitors Differs among Cells and Is Not Required for Its Inhibition" Molecules 25, no. 15: 3381. https://doi.org/10.3390/molecules25153381

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