Natural products triptolide, celastrol, and withaferin A inhibit the chaperone activity of peroxiredoxin i

Qian Zhao, Yu Ding, Zhangshuang Deng, On Yi Lee, Peng Gao, Pin Chen, Rebecca J. Rose, Hong Zhao, Zhehao Zhang, Xin Pei Tao, Albert J.R. Heck, Richard Kao, Dan Yang

Research output: Journal article publicationJournal articleAcademic researchpeer-review

17 Citations (Scopus)

Abstract

Peroxiredoxin I (Prx I) plays an important role in cancer development and inflammation. It is a dual-functional protein which acts as both an antioxidant enzyme and a molecular chaperone. While there have been intensive studies on its peroxidase activity, Prx I's chaperone activity remains elusive, likely due to the lack of chaperone inhibitors. Here we report that natural product triptolide selectively inhibits the chaperone activity of Prx I, but not its peroxidase activity. Through direct interaction with corresponding cysteines, triptolide triggers dissociation of high-molecular-weight oligomers of Prx I, and thereby inhibits its chaperone activity in a dose-dependent manner. We have also identified celastrol and withaferin A as novel Prx I chaperone inhibitors that are even more potent than triptolide in the chaperone activity assay. By revealing the exact molecular mechanisms of interaction and inhibition, the current study provides the first Prx I chaperone inhibitors as promising pharmacological tools for modulating and dissecting the chaperone function of Prx I.
Original languageEnglish
Pages (from-to)4124-4130
Number of pages7
JournalChemical Science
Volume6
Issue number7
DOIs
Publication statusPublished - 1 Jul 2015
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)

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