Signaling actions of electrophiles: anti-inflammatory therapeutic candidates

Abstract

Over the past several years, research on biologically relevant electrophiles has been replete with new insights, expanding our understanding of the roles electrophiles play in vivo. Importantly, many electrophiles can form reversible covalent adducts with both proteins and small-molecule thiols in cells. This post-translational protein modification has important ramifications, including changes in protein enzymatic activity, the transduction of signals within and between cells, and alterations in gene expression. Electrophiles modulate a variety of cellular signaling processes that are involved in several major diseases with inflammatory components. The electrophilic fatty-acid derivatives discussed in this work are naturally occurring products of redox reactions and enzymatic activity. Furthermore, several of these electrophilic species and their derivatives represent potential therapeutic candidates.

Figure 1. The β-carbons of nitroalkenes and α,β-unsaturated carbonyls are electrophilic

The chemical structures of a nitroalkene (left) and an α,β-unsaturated carbonyl (right) are represented above, in which “*” indicates an electrophilic β-carbon.

Figure 2

Chemical structures of electrophilic lipid derivatives.

Figure 3. Multiple mechanisms can lead to the nitration of lipids

A. Biologically relevant NO₂-FA products resulting from reaction of PUFA with NO_X and reactive oxygen species. B. Reactive intermediates from autoxidation of ^•NO and acidification of nitrite. Under aerobic conditions ^•NO can react rapidly with O₂ to form ^•NO₂. When the O₂ concentration is significantly lower than atmospheric conditions, ^•NO₂ and ^•NO can be in equilibrium with N₂O₃. In aqueous milieu, N₂O₃ can be in equilibrium with HNO₂. Finally, HNO₂ is in equilibrium with is conjugate base NO₂⁻ (pKa=3.35). As all of these reactions are reversible, their order and equilibria depend on the source and site of production of NO_X, the concentrations of various intermediates, and their reaction with other biomolecules.

Figure 4

Chemical structures of reactive electrophilic products of oxidation and electrophiles from dietary sources.

Figure 5

Chemical structures of oxidized lipids with anti-inflammatory signaling capabilities.

Figure 6

Chemical structures of electrophilic phytochemicals.

Figure 7. Modulation of cellular signaling mechanisms by electrophiles

Electophiles (E) can act at many loci within the cell. A. At the cellular membrane, electrophiles can modulate ion channel activity (e.g., adduction to essential cysteine residues of the TRP channel, thereby activating TRP signaling). Some adducts can be sequestered by reaction with glutathione (GSH), and GS-electrophile adducts can undergo further thiol exchange reactions or exit the cell via a multidrug resistant protein (MDR) mechanism. B. Cytosolic proteins can react with electrophiles, inducing changes in protein structure, activity, subcellular localization, or stability. An example of these outcomes is the modulation of protein kinase signaling by electrophiles and subsequent modulation of protein activity or gene regulation (see panel C). Electrophiles also affect signaling by influencing mitochondrial respiration and redox status, for example by reacting with cytochrome c. C. In the nucleus, transcription factors can react with electrophiles to affect the transcription of genes involved in cell survival, metabolism, and differentiation. During severe oxidative conditions, electrophiles can also form adducts with DNA and promote miscoding.