Cellular and Environmental Electrophiles: Balancing Redox Signaling, Inflammation, and Cell Death Pathways

Analogous to reversible phosphorylation of threonine, serine, and tyrosine residues as well established signal transduction mechanisms, the reversible oxidation of protein cysteine residues by reactive oxygen or nitrogen species, e.g. S-glutathionylation or S-nitrosylation, has emerged as an important mechanism of protein function regulation and cell signaling in relation to the activation of NADPH oxidases (NOX/DUOX enzymes) or nitric oxide synthases (NOSs). However, these key protein cysteine residues also present significant targets for a host of electrophilic compounds from either exogenous or endogenous sources. A number of α,β-unsaturated aldehydes and ketones have been identified as important environmental pollutants, bioactive components of ingested foods, or secondary mediators produced endogenously during oxidative processes and the addition of these electrophiles to cysteine thiols, a process known as S-alkylation, may represent an additional mode of “redox” signaling analogous to e.g. S-thiolation. In addition to mediating signals, α,β-unsaturated aldehydes and ketones may compete with or interfere with other pathways that feature thiol/redox dependent signaling. The biological effects of α,β-unsaturated aldehydes and ketones are determined largely by their relative electrophilic character, by acute effects on cellular GSH or redox status and direct S-alkylation of critical protein cysteines, and the activation of phase-2 enzymes involved in GSH synthesis and detoxification and elimination of these electrophiles. The cellular effects are thus determined by a balance between disposal, direct S-alkylation of critical protein targets and more indirect “oxidative stress responses” as a result of increased production of cellular oxidants, all of which are critical in determining apoptotic or necrotic cell death by α,β-unsaturated aldehydes, and their variable pro- and anti-inflammatory properties. The significance of α,β-unsaturated aldehydes as critical mediators of acute and/or chronic disease is gaining increased recognition, fueled by increased identification of critical biological targets for these electrophiles and observations of associations of polymorphisms in important detoxifying enzymes (glutathione S-transferases, GSTs) with chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD). This Chapter will address some of the general biochemical and cellular aspects of α,β-unsaturated aldehydes, and discuss mechanisms by which they can regulate cell death pathways and inflammatory responses and the importance of cellular defense mechanisms against these electrophiles.