Synthesis of Nitrolipids. All Four Possible Diastereomers of Nitrooleic Acids:  (<i>E</i>)- and (<i>Z</i>)-, 9- and 10-Nitro-octadec-9-enoic Acids

Woodcock, Steven R.; Marwitz, Adam J. V.; Bruno, Paulo Roberto de Abreu; Branchaud, Bruce P.

doi:10.1021/ol0613463

Cited by 48 publications

(43 citation statements)

References 34 publications

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“…Specific OA-NO 2 regioisomers were synthesized and purified as in Ref. 25. 15d-PGJ 2 was from Cayman Chemical Company (Ann Arbor, MI), and L-sulforaphane (SFN) was from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Kansanen

Bonacci

Schöpfer

et al. 2011

Journal of Biological Chemistry

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Nitro-fatty acids (NOIn this study, we investigate the molecular mechanisms by which 9-and 10-nitro-octadec-9-enoic acid (OA-NO 2 ) activate the transcription factor Nrf2, focusing on the post-translational modifications of cysteines in the Nrf2 inhibitor Keap1 by nitroalkylation and its downstream responses. Of the two regioisomers, 9-nitrooctadec-9-enoic acid was a more potent ARE inducer than 10-nitro-octadec-9-enoic acid. (2), the enzyme xanthine oxidoreductase (3), and the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) (4). Moreover, NO 2 -FAs activate heat shock (5) and antioxidant response pathways (5, 6) via mechanisms that remain to be defined. Antioxidant response element (ARE)-regulated genes play an essential role in the protection against endogenous and exogenous stresses (7). The transcription factor nuclear factor E2-related factor-2 (Nrf2) can activate these genes via binding to AREs as a heterodimer with small Maf proteins (7). Under basal conditions, Nrf2 is bound to its inhibitor Kelch-like ECHassociated protein 1 (Keap1), which functions as an adaptor molecule in the Cul3-based E3 ligase complex. Nrf2 is then rapidly ubiquitinated and degraded (8, 9). During periods when cellular concentrations of oxidative or electrophilic species are elevated, the interaction of Nrf2 with the ubiquitin ligase complex is disrupted, enabling the escape of Nrf2 from degradation, its nuclear translocation, and transactivation of target genes.Keap1 is a Cys-rich protein with 27 Cys residues in the human and 25 Cys residues in the murine protein. Keap1 has four functional domains: the Bric-a-Brac, tramtrack, broad complex (BTB) domain, the intervening region (IVR), the Kelch domain (also known as the double glycine repeat), and the C-terminal region. Alkylation or oxidation of Keap1 Cys residues, predominantly within the IVR, leads to the inactivation of Keap1 and is the central mechanism for the activation of Nrf2 (10 -12). A number of studies utilizing mass spectrometry (MS) analysis show that electrophilic inducers of Nrf2 modify several different Cys residues in recombinant Keap1. These data indi-* This work was supported, in whole or in part, by National Institutes of Health BTB, Bric-a-Brac, tramtrack, broad complex; IVR, intervening region; 15d-PGJ 2 , 15-deoxy-⌬12,14-prostaglandin J 2 ; HEK, human embryonic kidney; ␤-ME, ␤-mercaptoethanol; OA-NO 2 , 9-and 10-nitro-octadec-9-enoic acid; 9-OA-NO 2 , 9-nitro-octadec-9-enoic acid; 10-OA-NO 2 , 10-nitro-octadec-9-enoic acid; LNO 2 , 9-, 10-, 12-, or 13-nitro-octadeca-9,12-dienoic acid.

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“…Specific OA-NO 2 regioisomers were synthesized and purified as in Ref. 25. 15d-PGJ 2 was from Cayman Chemical Company (Ann Arbor, MI), and L-sulforaphane (SFN) was from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Kansanen

Bonacci

Schöpfer

et al. 2011

Journal of Biological Chemistry

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182

184

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“…The specific regioisomer 9-nitro-9-cis-octadecenoic acid (C 9 -OA-NO 2 ) was synthesized as described (41). Linoleic and oleic acids were from Nu-Check Prep (Elysian, MN).…”

Section: Methodsmentioning

confidence: 99%

Nitro-fatty Acid Reaction with Glutathione and Cysteine

Baker

Golin-Bisello

et al. 2007

Journal of Biological Chemistry

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178

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Fatty acid nitration by nitric oxide-derived species yields electrophilic products that adduct protein thiols, inducing changes in protein function and distribution. Nitro-fatty acid adducts of protein and reduced glutathione (GSH) are detected in healthy human blood. Kinetic and mass spectrometric analyses reveal that nitroalkene derivatives of oleic acid (OA-NO 2 ) and linoleic acid (LNO 2 ) rapidly react with GSH and Cys via Michael addition reaction. Rates of OA-NO 2 and LNO 2 reaction with GSH, determined via stopped flow spectrophotometry, displayed second-order rate constants of 183 M ؊1 s ؊1 and 355 M ؊1 s ؊1 , respectively, at pH 7.4 and 37°C. These reaction rates are significantly greater than those for GSH reaction with hydrogen peroxide and non-nitrated electrophilic fatty acids including 8-iso-prostaglandin A 2 and 15-deoxy-⌬ 12,14 -prostaglandin J 2 . Increasing reaction pH from 7.4 to 8.9 enhanced apparent second-order rate constants for the thiol reaction with OA-NO 2 and LNO 2 , showing dependence on the thiolate anion of GSH for reactivity. Rates of nitroalkene reaction with thiols decreased as the pK a of target thiols increased. Increasing concentrations of the detergent octyl-␤-D-glucopyranoside decreased rates of nitroalkene reaction with GSH, indicating that the organization of nitro-fatty acids into micellar or membrane structures can limit Michael reactivity with more polar nucleophilic targets. In aggregate, these results reveal that the reversible adduction of thiols by nitro-fatty acids is a mechanism for reversible post-translational regulation of protein function by nitro-fatty acids.

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“…by nucleophilic substitution of [ 15 N]labeled sodium nitrate and 1-bromononane-6,6,7,7-d 4 ) and a nine-carbon aldehyde-ester via a previously described nitroaldol procedure (21,22 (21). DMEM, FBS, HBSS, and antibiotic-antimycotic solutions were from Corning Cellgro (Herndon, VA).…”

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Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

Fazzari

Khoo

Woodcock

et al. 2017

Journal of Lipid Research

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inflammatory and metabolic stress (1-3). In particular, the reaction between unsaturated FAs and the nitric oxide and nitrite (NO 2  )-derived radical species nitrogen dioxide (·NO 2 ) generates electrophilic FA nitro-alkene byproducts (NO 2 -FAs) (4). These molecules are endogenously detected and have been observed to mediate salutary responses in models of inflammatory injury and oxidative stress. Current data supports that NO 2 -FAs predominantly signal via posttranslational protein modifications, specifically of functionally significant Cys residues of nuclear transcription factor erythroid 2-related factor 2 (Nrf2), soluble epoxide hydrolase (sEH), p65 subunit of nuclear factor kappa B (NF-kB), transient receptor potential cation channel subfamily V member 1 (TRPV1), and heat shock factor-1 (HSF-1) (5-9).NO 2 -FAs have been detected in a variety of species, including mammals and plants, as both free acid and as complex lipid-esterified species (3, 10, 11). For example, NO 2 -FAs are detected at micromolar concentrations in rodent cardiac mitochondria subjected to an episode of ischemia-reperfusion and at nanomolar concentrations in healthy human plasma and urine (12)(13)(14). Additionally, [D 4 ]octadecenoic acid; Nrf2, nuclear transcription factor erythroid 2-related factor 2; OA, oleic acid; PC, phosphatidylcholine; QWBA, quantitative whole-body autoradiography; sEH, soluble epoxide hydrolase; TAG, triacylglyceride. The designations "9-NO 2 -" and "10-NO 2 -"OA are used herein to describe the position of the nitro group in the fatty acid chain and do not refer to IUPAC nomenclature. MED Foundation (M.F.), National Institutes of Health Grants R01-AT006822 (F.J.S.), R01-HL64937, R01-HL132550, and P01-HL103455 (B.A.F.), and American Heart Association Grant 14GRNT20170024 (F.J.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the1 To whom correspondence should be addressed. e-mail: freerad@pitt.edu (B.A.F.); fjs2@pitt.edu (F.J.S.) The online version of this article (available at http://www.jlr.org) contains a supplement.

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Synthesis of Nitrolipids. All Four Possible Diastereomers of Nitrooleic Acids: (E)- and (Z)-, 9- and 10-Nitro-octadec-9-enoic Acids

Cited by 48 publications

References 34 publications

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Nitro-fatty Acid Reaction with Glutathione and Cysteine

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

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