Intracellular hydrolysis of small-molecule O-linked N-acetylglucosamine transferase inhibitors differs among cells and is not required for its inhibition

Loi, Elena Maria (author), Weiss, Matjaž (author), Pajk, Stane (author), Gobec, Martina (author), Tomašič, Tihomir (author), Pieters, Roland J. (author), Anderluh, Marko (author)

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.

• Language: English
• Keywords: ester hydrolysis, inhibitor, O-GlcNAc transferase, OGT inhibitor
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 10 str.
• Numbering: Vol. 25, iss. 15, art. 3381
• PID: 20.500.12556/RUL-133856
• UDC: 577.121:615
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules25153381
• COBISS.SI-ID: 24851459
• Publication date in RUL: 17.12.2021

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 01.08.2020

Secondary language

• Language: Slovenian
• Keywords: terapevtska uporaba, metaboliti