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

Sci Rep. 2019 Sep 5;9(1):12801. doi: 10.1038/s41598-019-48888-6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catechin / analogs & derivatives*
  • Catechin / chemistry
  • Catechin / pharmacology
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • HEK293 Cells
  • Humans
  • Proliferating Cell Nuclear Antigen / chemistry
  • Structure-Activity Relationship
  • Tea / chemistry*
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors
  • Ubiquitin-Activating Enzymes / chemistry*
  • Ubiquitination* / drug effects

Substances

  • Flavonoids
  • Proliferating Cell Nuclear Antigen
  • Tea
  • UBA1 protein, human
  • myricetin
  • Catechin
  • epigallocatechin gallate
  • Ubiquitin-Activating Enzymes