Multilevel structure–activity profiling reveals multiple green tea compound families that each modulate ubiquitin-activating enzyme and ubiquitination by a distinct mechanism

Gabriel Fenteany, Paras Gaur, Lili Hegedűs, Kata Dudás, Ernő Kiss, Edit Wéber, László Hackler, T. Martinek, L. Puskás, Lajos Haracska

Research output: Contribution to journalArticle

Abstract

We developed and implemented a reconstituted system to screen for modulators of the ubiquitination of proliferating cell nuclear antigen, a process that activates pathways of DNA damage tolerance and drug resistance. We identified the primary putatively health-beneficial green tea polyphenol epigallocatechin gallate (EGCG) and certain related small molecules as potent inhibitors of ubiquitination. EGCG directly and reversibly targets the ubiquitin-activating enzyme Uba1, blocking formation of the Uba1~ubiquitin thioester conjugate and thus ubiquitination and in the cell. Structure–activity relationship profiles across multiple biochemical and cellular assays for a battery of EGCG analogues revealed distinct chemical and mechanism-of-action clusters of molecules, with catechin gallates, alkyl gallates, and myricetin potently inhibiting ubiquitination. This study defines a number of related though distinct first-in-class inhibitors of ubiquitination, each series with its own unique activity pattern and mechanistic signature.

Original languageEnglish
Article number12801
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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Ubiquitin-Activating Enzymes
Ubiquitination
Tea
Pharmacologic Actions
Proliferating Cell Nuclear Antigen
Polyphenols
Ubiquitin
Drug Resistance
DNA Damage
Health
epigallocatechin gallate

ASJC Scopus subject areas

  • General

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Multilevel structure–activity profiling reveals multiple green tea compound families that each modulate ubiquitin-activating enzyme and ubiquitination by a distinct mechanism. / Fenteany, Gabriel; Gaur, Paras; Hegedűs, Lili; Dudás, Kata; Kiss, Ernő; Wéber, Edit; Hackler, László; Martinek, T.; Puskás, L.; Haracska, Lajos.

In: Scientific reports, Vol. 9, No. 1, 12801, 01.12.2019.

Research output: Contribution to journalArticle

Fenteany, Gabriel ; Gaur, Paras ; Hegedűs, Lili ; Dudás, Kata ; Kiss, Ernő ; Wéber, Edit ; Hackler, László ; Martinek, T. ; Puskás, L. ; Haracska, Lajos. / Multilevel structure–activity profiling reveals multiple green tea compound families that each modulate ubiquitin-activating enzyme and ubiquitination by a distinct mechanism. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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