Generation of pyrroles in the reaction of Levuglandin E2 with proteins

Iyer, Rajkumar S.; Kobierski, Michael E.; Salomon, Robert G.

doi:10.1021/jo00099a039

Cited by 49 publications

(40 citation statements)

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“…We previously reported chemical evidence for the initial formation of pyrroles that incorporate the ⑀-amino group of protein lysyl residues (15). Our recent studies employing mass spectral detection of lipidmodified lysine uncovered the facile oxidation of LGE 2 -derived pyrroles leading to lactam and hydroxylactam derivatives, and confirmed that isoLG-derived lysyl group modifications are present in oxLDL (19).…”

Section: Fig 13 the Iso[n]supporting

confidence: 52%

“…An Ehrlich pyrrole assay (40,41) was performed to determine the concentration of protein-bound iso [4]LGE 2 -derived pyrroles as described previously for determining the concentration of LGE 2 -derived pyrroles (15,27). Tritium-labeled LGE 2 -HSA and LGE 2 -BSA were used as a standards for the assay.…”

Section: -Protein Adductsmentioning

confidence: 99%

“…We previously showed that for high LGE 2 /protein ratios, Paal-Knorr condensation of LGE 2 with ⑀-amino groups of lysyl residues of proteins gives mainly LGE 2 -derived protein-bound pyrrole (21). Earlier studies also demonstrated that quantitative analysis of LGE 2 -derived protein-bound pyrroles can be accomplished using the Ehrlich assay that measures the absorbance of a blue-green chromophore generated by the condensation of LGE 2 -pyrrole with DMAB (15).…”

Section: Elisamentioning

confidence: 99%

“…1), these seco prostanoic acids are cogenerated with prostaglandins (PGs) (11)(12)(13) by rearrangements of the endoperoxide PGH 2 which occur readily (t1 ⁄2 ϭ 5 min at 37°C) under the conditions of its cyclooxygenase (COX)-promoted biosynthesis from arachidonic acid (AA). LGE 2 binds avidly with proteins (14) forming a protein-bound pyrrole, LGE 2 -pyrrole (15), as well as protein-protein (16,17) and DNA-protein (18) crosslinks. We recently reported mass spectral characterization of several lysine-based modifications that are generated by covalent adduction of LGE 2 with proteins (19).…”

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confidence: 99%

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Protein Adducts of Iso[4]levuglandin E2, a Product of the Isoprostane Pathway, in Oxidized Low Density Lipoprotein

Salomon

Wang

Brame

et al. 1999

Journal of Biological Chemistry

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Levuglandin (LG) E 2 , a cytotoxic seco prostanoic acid co-generated with prostaglandins by nonenzymatic rearrangements of the cyclooxygenase-derived endoperoxide, prostaglandin H 2 , avidly binds to proteins. That LGE 2 -protein adducts can also be generated nonenzymatically is demonstrated by their production during free radical-induced oxidation of low density lipoprotein (LDL). Like oxidized LDL, LGE 2 -LDL, but not native LDL, undergoes receptor-mediated uptake and impaired processing by macrophage cells. Since radicalinduced lipid oxidation produces isomers of prostaglandins, isoprostanes (isoPs), via endoperoxide intermediates, we postulated previously that a similar family of LG isomers, isoLGs, is cogenerated with isoPs. Now iso[4]LGE 2 -protein epitopes produced by radicalinduced oxidation of arachidonic acid in the presence of protein were detected with an enzyme-linked immunosorbent assay. Iso[4]LGE 2 -protein epitopes are also generated during free radical-induced oxidation of LDL. All of the LGE 2 isomers generated upon oxidation of LDL are efficiently sequestered by covalent adduction with LDL-based amino groups. The potent electrophilic reactivity of iso-LGs can be anticipated to have biological consequences beyond their obvious potential as markers for specific arachidonate-derived protein modifications that may be of value for the quantitative assessment of oxidative injury.

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Section: Fig 13 the Iso[n]supporting

confidence: 52%

Section: -Protein Adductsmentioning

confidence: 99%

Section: Elisamentioning

confidence: 99%

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confidence: 99%

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Protein Adducts of Iso[4]levuglandin E2, a Product of the Isoprostane Pathway, in Oxidized Low Density Lipoprotein

Salomon

Wang

Brame

et al. 1999

Journal of Biological Chemistry

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“…These findings highlight a potential functional role for the oxygenated dioxabicyclo[3.2.1]octanone as a masked 1,4-dialdehyde progenitor leading to a protein bound pyrrole species. The reaction of 1,4-dicarbonyl compounds with lysine residues to form pyrrole-protein conjugates has been proposed as the origin of cellular toxicity of n hexane via in vivo formation of 2,5-hexadione and levuglandin E 2 , a δ-keto aldehyde derived from the prostaglandin precursor endoperoxide H 2 (40,41). An additional feature, apparent from the observed formation of 26 and 27, is the role of the C12 acetoxy group as a latent leaving group enabling the formation of structures that possess two sites of covalent modifications via pyrrole formation and subsequent C12 reactivity.…”

Section: Effects Of Mace and Its T-butyl Analog On Golgi Organizationmentioning

confidence: 99%

Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core

Schnermann

Beaudry

Egorova

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Golgi-modifying properties of the spongian diterpene macfarlandin E (MacE) and a synthetic analog, t-Bu-MacE, containing its 2,7-dioxabicyclo[3.2.1]octan-3-one moiety are reported. Natural product screening efforts identified MacE as inducing a novel morphological change in Golgi structure defined by ribbon fragmentation with maintenance of the resulting Golgi fragments in the pericentriolar region. t-Bu-MacE, which possesses the substituted 2,7-dioxabicyclo[3.2.1]octan-3-one but contains a tert-butyl group in place of the hydroazulene subunit of MacE, was prepared by chemical synthesis. Examination of the Golgi-modifying properties of MacE, t-Bu-MacE, and several related structures revealed that the entire oxygen-rich bridged-bicyclic fragment is required for induction of this unique Golgi organization phenotype. Further characterization of MacE-induced Golgi modification showed that protein secretion is inhibited, with no effect on the actin or microtubule cytoskeleton being observed. The conversion of t-Bu-MacE and a structurally related des-acetoxy congener to substituted pyrroles in the presence of primary amines in protic solvent at ambient temperatures suggests that covalent modification might be involved in the Golgi-altering activity of MacE.organelle organization | chemical biology | natural product | reactivity

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Formation of Aldehydes and Ketones by Rearrangements

Larock

Dubrovskiy

Markina

2018

Comprehensive Organic Transformations

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Isomerization Epoxides Vinylic Ethers Pinacol and Related Rearrangements Ring Rearrangement Ring Opening Ring Contraction Ring Expansion Electrocyclic Rearrangements Miscellaneous Rearrangements

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Generation of pyrroles in the reaction of Levuglandin E2 with proteins

Cited by 49 publications

References 0 publications

Protein Adducts of Iso[4]levuglandin E2, a Product of the Isoprostane Pathway, in Oxidized Low Density Lipoprotein

Protein Adducts of Iso[4]levuglandin E2, a Product of the Isoprostane Pathway, in Oxidized Low Density Lipoprotein

Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core

Formation of Aldehydes and Ketones by Rearrangements

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