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The Adductomics of Isolevuglandins: Oxidation of IsoLG Pyrrole Intermediates Generates Pyrrole–Pyrrole Crosslinks and Lactams

1
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
2
Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
*
Author to whom correspondence should be addressed.
High-Throughput 2019, 8(2), 12; https://doi.org/10.3390/ht8020012
Received: 2 March 2019 / Revised: 6 May 2019 / Accepted: 8 May 2019 / Published: 10 May 2019
(This article belongs to the Special Issue Adductomics: Elucidating the Environmental Causes of Disease)
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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.
Keywords: Adductome; Covalent adducts; Electrophilic species; Mass spectrometry; Reactive metabolites; Isolevuglandins; Protein crosslinking Adductome; Covalent adducts; Electrophilic species; Mass spectrometry; Reactive metabolites; Isolevuglandins; Protein crosslinking
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Bi, W.; Jang, G.-F.; Zhang, L.; Crabb, J.W.; Laird, J.; Linetsky, M.; Salomon, R.G. The Adductomics of Isolevuglandins: Oxidation of IsoLG Pyrrole Intermediates Generates Pyrrole–Pyrrole Crosslinks and Lactams. High-Throughput 2019, 8, 12.

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