title: Chemical and biological mechanisms of phytochemical activation of Nrf2 and importance in disease prevention.
abstract: Plants are an incredibly rich source of compounds that activate the Nrf2 transcription factor, leading to upregulation of a battery of cytoprotective genes. This perspective surveys established and proposed molecular mechanisms of Nrf2 activation by phytochemicals with a special emphasis on a common chemical property of Nrf2 activators: the ability as "soft" electrophiles to modify cellular thiols, either directly or as oxidized biotransformants. In addition, the role of reactive oxygen/nitrogen species as secondary messengers in Nrf2 activation is discussed. While the uniquely reactive C151 of Keap1, an Nrf2 repressor protein, is highlighted as a key target of cytoprotective phytochemicals, also reviewed are other stress-responsive proteins, including kinases, which play non-redundant roles in the activation of Nrf2 by plant-derived agents. Finally, the perspective presents two key factors accounting for the enhanced therapeutic windows of effective phytochemical activators of the Keap1-Nrf2 axis: enhanced selectivity toward sensor cysteines and reversibility of addition to thiolate molecules.
authors: Department of Chemistry, Villanova University, 215a Mendel Science Hall, 800 Lancaster Avenue, Villanova, PA 19085.
authors: Aimee L
authors: AL
authors: Eggler
authors: Purdue University Center for Cancer Research, West Lafayette, Indiana, 47907.
authors: Sergey N
authors: SN
authors: Savinov