PYDDT, a novel phase 2 enzymes inducer, activates Keap1-Nrf2 pathway via depleting the cellular level of glutathione.
Keap1-Nrf2 pathway has emerged as a regulator for the endogenous antioxidant response, which is critical in defending cells against carcinogenesis. Herein, we demonstrated that depleting the cellular level of glutathione (GSH) by a novel electrophilic agent 2-(pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3-diynyl) thiophene (PYDDT) could activate Keap1-Nrf2 pathway. In above process, it was found that Keap1 was modified by S-glutathionylation, an important post-translational modification of protein cysteines with critical roles in oxidative stress and signal transduction. We concluded from our findings that conjugation with intracellular GSH by PYDDT might lead to Keap1 S-glutathionylation and was a key event involved in its Nrf2 inducing activity.
Zhang
Xiaoyu
X
School of Pharmaceutical Sciences, Zhejiang University, Zijingang Campus, No. 388 Yuhangtang Rd, Hangzhou 310058, PR China.
Zhao
Xiaofeng
X
Ma
Zhongjun
Z
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D004365:Drugs, Chinese Herbal / Q000737:chemistry; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D050217:Metabolic Detoxication, Phase II; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects*; D010936:Plant Extracts / Q000494:pharmacology; D010946:Plants, Medicinal / Q000737:chemistry; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*
C552929:2-(pro-1-ynyl)-5-(5,6-dihydroxypenta-1,3-diynyl)thiophene; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D004365:Drugs, Chinese Herbal; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D013876:Thiophenes; D005978:Glutathione