Protein modifications by electrophilic lipoxidation products: Adduct formation, chemical strategies and tandem mass spectrometry for their detection and identification

Abstract

The post-translational modification of proteins by electrophilic oxylipids is emerging as an important mechanism that contributes to the complexity of proteomes. Enzymatic and nonenzymatic oxidation of biological lipids results in the formation of chemically diverse electrophilic carbonyl compounds, such as 2-alkenals and 4-hydroxy alkenals, epoxides and eicosanoids with reactive cyclopentenone structures. These lipoxidation products are capable of modifying proteins. Originally considered solely as markers of oxidative insult, more recently the modifications of proteins by lipid peroxidation products are being recognized as a new mechanism of cell signaling with relevance to redox homeostasis, adaptive response and inflammatory resolution. The growing interest in protein modifications by reactive oxylipid species necessitates the availability of methods that are capable of detecting, identifying and characterizing these protein adducts in biological samples with high complexity. However, the efficient analysis of these chemically diverse proteins presents a considerable analytical challenge. We first provide an introduction into the chemistry and biological relevance of the protein adduction by electrophilic lipoxidation products. We then provide an overview of tandem mass spectrometry approaches that have been developed in recent years for the interrogation of protein modifications by electrophilic oxylipid species.

Cross-talk between lipid and protein carbonylation in a dynamic cardiomyocyte model of mild nitroxidative stress

“…Presence of the second carbonyl function (assuming it is in α position) results in a higher electrophilicity of the first carbonyl group. Indeed, glyoxal, shown here as the most reactive oxoLPP (15 modification sites), was recently classified as aldehyde with the highest calculated electrophilicity and softness [97], followed by HNE, MDA and HHE [98], which closely resembled the reactivity detected in our study (nine, ten and five modification sites for HNE, methylglyoxal/MDA and HHE respectively). One more reason for the high reactivity of short chain dicarbonyls could be the relatively high hydrophilicity.…”

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…369–373 The cyclopentenone-like eicosanoid electrophile, 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ2), was reported to localize in mitochondria and is responsible for inducing ROS formation in endothelial cells. 374 However, previous work has shown that protein targets of 15d-PGJ2 are found in different sites in the cell, including the cytosol and mitochondria, evidencing the pleiotropic nature of the cyclopentenone.…”

Interrelation Between Oxidative Carbonylation of Proteins and Lysosomal Proteolysis of Plasma in Experimentally Modelledischemia and Ischemia-Reperfusion

“…В свою очередь, протеолитические системы признаются одним из возможных механизмов защиты от накопления окис лительно модифицированных белков и совершенным регулятором протеинового обмена [3,4]. Кроме этого, лизосомаль-ные протеиназы являются важными фак торами развития сердечно-сосудистых за болеваний, в том числе ассоциированных с воспалением [5].…”

“…Fortheir turn, proteolytic systems are regarded as one of probable protective mech anisms against accumulation of oxidatively modified proteins and as a perfect controller of protein metabolism [3,4]. Besides, lysosomal proteinases are important factors for development of cardiovascular diseases including those associated with inflammation [5].…”