Abstract
Isoprostane endoperoxides generated by free radical-induced oxidation of arachidonates, and prostaglandin endoperoxides generated through enzymatic cyclooxygenation of arachidonate, rearrange nonenzymatically to isoprostanes and a family of stereo and structurally isomeric γ-ketoaldehyde seco-isoprostanes, collectively known as isolevuglandins (isoLGs). IsoLGs are stealthy toxins, and free isoLGs are not detected in vivo. Rather, covalent adducts are found to incorporate lysyl ε-amino residues of proteins or ethanolamino residues of phospholipids. In vitro studies have revealed that adduction occurs within seconds and is uniquely prone to cause protein–protein crosslinks. IsoLGs accelerate the formation of the type of amyloid beta oligomers that have been associated with neurotoxicity. Under air, isoLG-derived pyrroles generated initially are readily oxidized to lactams and undergo rapid oxidative coupling to pyrrole–pyrrole crosslinked dimers, and to more highly oxygenated derivatives of those dimers. We have now found that pure isoLG-derived pyrroles, which can be generated under anoxic conditions, do not readily undergo oxidative coupling. Rather, dimer formation only occurs after an induction period by an autocatalytic oxidative coupling. The stable free-radical TEMPO abolishes the induction period, catalyzing rapid oxidative coupling. The amine N-oxide TMAO is similarly effective in catalyzing the oxidative coupling of isoLG pyrroles. N-acetylcysteine abolishes the generation of pyrrole–pyrrole crosslinks. Instead pyrrole-cysteine adducts are produced. Two unified single-electron transfer mechanisms are proposed for crosslink and pyrrole-cysteine adduct formation from isoLG-pyrroles, as well as for their oxidation to lactams and hydroxylactams.
Highlights
The prostaglandin endoperoxide intermediate PGH2 of the cyclooxygenase pathway, and its stereo and structural isomers, e.g., the isoprostane endoperoxides isoPGH2 or iso[4]PGH2, which are generated as phospholipid esters through free radical-induced oxidation of arachidonyl phospholipids, spontaneously rearrange to produce various stereo and structurally isomeric γ-ketoaldehydes (Scheme 1), referred to collectively as isolevuglandins
The present study established that, (1) pure isoLG pyrroles are inherently unreactive toward oxidation by air, but are susceptible to an autocatalytic acceleration of the reaction, (2) an electrophilic cation radical produced by electron transfer from an electron-rich isoLG-pyrrole to oxygen can be intercepted by the nucleophilic thiol of N-acetylcysteine, and (3) oxidative transformations of isoLG pyrroles are promoted by single electron transfer catalysts
If that oligomerization involves oxidative coupling of isoLG pyrroles, it is expected to be prevented under the anoxic in vitro conditions established in the present study
Summary
The prostaglandin endoperoxide intermediate PGH2 of the cyclooxygenase pathway, and its stereo and structural isomers, e.g., the isoprostane endoperoxides isoPGH2 or iso[4]PGH2, which are generated as phospholipid esters through free radical-induced oxidation of arachidonyl phospholipids, spontaneously rearrange to produce various stereo and structurally isomeric γ-ketoaldehydes (Scheme 1), referred to collectively as isolevuglandins (isoLGs). Covalent adduction of isoLGs to proteins occurs within seconds. The adducts include derivatives of isoLGs that incorporate the. High-Throughput 2019, 8, 12 High-Throughput 2019, 8, 12. 2 of 15 2 of 16 εth-aamt iinncoorgproourapteotfhperoεt-eaimnilnyosyglroreuspidoufeps rionteainpylyrrsoyllerreisnidg.ueTshienseaepleycrtrroolne-rriinchg.pTyhreroseleeslaecretrorena-driiclhy opxyirdriozleeds taorfeorrmealdaicltyamoxsiadnizdehdydtoroxfoyrlamctalamcstatmhast aarnedthheymdarojoxryilsaocLtaGmdsertihvaattivaerse otfhperomteainjosrinisvoiLvGo. Cdeorviavlaetnivt easddoufctpiorontoefinissoLinGsvaivlsoo. Coupling of isoLG-derived pyrroles (Scheme 1) [2]. Biosynntthesis of isolevuglandins and their covalent adduction to proteins
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