Synthesis of a Pyrazole Isostere of Pyrroles Formed by the Reaction of the .epsilon.-Amino Groups of Protein Lysyl Residues with Levuglandin E2

Kobierski, Michael E.; Kim, Seokchan; Murthi, Krishna K.; Iyer, Rajkumar S.; Salomon, Robert G.

doi:10.1021/jo00099a040

Cited by 18 publications

(22 citation statements)

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“…As mentioned above, we noted the possibility that an isoLG identical with LGE 2 may be formed in vivo by nonenzymatic phospholipid peroxidation through rearrangement of intermediate isoprostane endoperoxides, and therefore, protein adducts detected in vivo with our anti-LGE 2 protein antibodies might not be products of the COX pathway [20]. Confirmation of this hypothesis and our discovery of IsoLGs soon followed with the demonstration that LGE 2 -protein adducts are generated upon free radical-induced oxidation of LDL [23].…”

Section: Becausesupporting

confidence: 75%

“…However, we cautioned that these studies could not distinguish between a COX-dependent origin and a possible alternative free radical-induced autoxidative biogenesis. Thus, we envisioned that the epitopes recognized by LGE 2 -protein adduct antibodies could also be generated by free radical-induced cyclooxygenation of arachidonyl phospholipids [20]. This possibility was suggested by chemistry discovered in the late sixties that results in the generation of stereo and structural isomers of prostaglandins [21] LGs form covalent adducts with proteins.…”

Section: Becausementioning

confidence: 99%

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Oxidized phospholipids, isolevuglandins, and atherosclerosis

Zhang

Salomon²

2005

Mol. Nutr. Food Res.

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Autoxidation of polyunsaturated phosphatidylcholines (PCs) generates isolevuglandins (isoLGs) through rearrangements of isoprostanoid endoperoxides. Within seconds, isoLGs are sequestered by covalent adduction with proteins. Murine plasma isoLG-protein levels increased at least 2.5-fold in response to inflammation. IsoLG-protein adducts accumulate in vivo providing a convenient dosimeter of oxidative stress. Elevated blood isoLG-protein levels present in atherosclerosis (AS) patients point to an independent defect that is not associated with total cholesterol levels, which results in an abnormally high level of oxidative injury in AS. Protein adduction and cross-linking caused by isoLGs can obstruct protein function. For example, it interferes with proteosomal degradation of proteins and, consequently, may result in apoptotic death of smooth muscle cells and destabilization of atherosclerotic plaques. Phospholipid autoxidation also generates biologically active oxidatively truncated PCs through fragmentation of dihydroperoxydienes that can be promoted by alpha-tocopherol. The oxidatively truncated PCs in oxidized low-density lipoprotein (oxLDL) contribute to the etiology of AS by inhibiting enzymatic activities required for normal processing of oxLDL by macrophages. They promote interactions of monocytes with endothelial cells that may foster migration of monocytes into the subendothelial space. They are also ligands for unregulated receptor-mediated uptake of oxLDL by monocyte macrophages leading to foam cell formation.

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Section: Becausesupporting

confidence: 75%

Section: Becausementioning

confidence: 99%

Oxidized phospholipids, isolevuglandins, and atherosclerosis

Zhang

Salomon²

2005

Mol. Nutr. Food Res.

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“…6 They form covalent adducts with orders of magnitude greater avidity than other lipid oxidation products such as 4-hydroxynonenal and malondialdehyde (MDA). 7–9 These adducts incorporate the primary amino group in a pyrrole ring that is readily oxidized to lactam and hydroxylactam derivatives. 10 IsoLG-protein adduction has potential biological consequences.…”

Section: Introductionmentioning

confidence: 99%

Molecular Structures of Isolevuglandin-Protein Cross-Links

Jang

Zhang

et al. 2016

Chem. Res. Toxicol.

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Isolevuglandins (isoLGs) are stereo and structurally isomeric γ-ketoaldehydes produced through free radical-induced oxidation of arachidonates. Some isoLG isomers are also generated through enzymatic cyclooxygenation. Post-translational modification of proteins by isoLG is associated with loss-of-function, cross-linking and aggregation. We now report that a low level of modification by one or two molecules of isoLG has a profound effect on the activity of a multi subunit protease, calpain-1. Modification of one or two key lysyl residues apparently suffices to abolish catalytic activity. Covalent modification of calpain-1 led to intersubunit cross-linking. Hetero- and homo-oligomers of the catalytic and regulatory subunits of calpain-1 were detected by SDS PAGE with Western blotting. N-Acetyl-glycyl-lysine methyl ester and β-amyloid(11-17) peptide EVHHQKL were used as models for characterizing the cross-linking of protein lysyl residues resulting from adduction of iso[4]LGE2. Aminal, bispyrrole and trispyrrole cross-links of these two peptides were identified and fully characterized by mass spectrometry. Aminal and bispyrrole dimers were both detected. Furthermore, a complex mixture of derivatives of the bispyrrole cross-link containing one or more additional atoms of oxygen was found. Interesting differences are evident in the predominant crosslink type generated in the reaction of iso[4]LGE2 with these peptides. More aminal cross-link versus bispyrrole is formed during reaction of the dipeptide with iso[4]LGE2. In contrast, more bispyrrole versus aminal cross-link is formed during the reaction of EVHHQKL with iso[4]LGE2. It is tempting to speculate that the EVHHQKL peptide-pyrrole modification forms noncovalent aggregates that favor the production of covalent bispyrrole cross-links because β-amyloid(11-17) tends to spontaneously oligomerize.

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“…Because LGE 2 -derived pyrroles are unstable, we prepared a pyrazole isostere (Fig. 4) of LGE 2 -derived protein-bound pyrrole to serve as stable well defined antigen (52). As expected, immunoreactivity detectable with antibodies raised against the isostere was generated upon reaction of LGE 2 with proteins (25).…”

Section: Immunoassays For Lge 2 -Protein Adductsmentioning

confidence: 88%

Levuglandins and Isolevuglandins: Stealthy Toxins of Oxidative Injury

Salomon

2005

Antioxidants & Redox Signaling

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Inspired by a reaction discovered through basic research on the chemistry of the bicyclic peroxide nucleus of the prostaglandin endoperoxide PGH2, we postulated that levulinaldehyde derivatives with prostaglandin side chains, levuglandins (LGs), and structurally isomeric analogues, isolevuglandins (iso[n]LGs), would be generated by nonenzymatic rearrangements of prostanoid and isoprostanoid endoperoxides. Two decades of subsequent studies culminated in our discoveries of the LG and isoLG pathways, branches of the cyclooxygenase and isoprostane pathways, respectively. In cells, PGH2 rearranges nonenzymatically to LGs even in the presence of enzymes that use PGH2 as a substrate. IsoLGs, also known as isoketals or neuroketals, are generated in vivo through free radical-induced autoxidation of polyunsaturated phospholipid esters. Hydrolysis occurs after rapid adduction of isoLG phospholipids to proteins. The proclivity of these reactive species to avidly bind covalently with and cross-link proteins and nucleic acids complicated the hunt for LGs and isoLGs in vivo. The extraordinary reactivity of these "stealthy toxins" underlies much, if not all, of the biological consequences of LG and isoLG generation. They interfere with protein function and are among the most potent neurotoxic products of lipid oxidation known. Because they can accumulate over the lifetimes of proteins, iso[n]LG-protein adducts represent a convenient dosimeter of oxidative stress.

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Synthesis of a Pyrazole Isostere of Pyrroles Formed by the Reaction of the .epsilon.-Amino Groups of Protein Lysyl Residues with Levuglandin E2

Cited by 18 publications

References 0 publications

Oxidized phospholipids, isolevuglandins, and atherosclerosis

Oxidized phospholipids, isolevuglandins, and atherosclerosis

Molecular Structures of Isolevuglandin-Protein Cross-Links

Levuglandins and Isolevuglandins: Stealthy Toxins of Oxidative Injury

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