The Experts below are selected from a list of 597 Experts worldwide ranked by ideXlab platform
Francisco J Schopfer - One of the best experts on this subject based on the ideXlab platform.
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Electrophilic fatty acid Nitroalkenes regulate Nrf2 and NF-κB signaling:A medicinal chemistry investigation of structure-function relationships
Scientific Reports, 2018Co-Authors: Nicholas K. H. Khoo, Francisco J Schopfer, Sonia R. Salvatore, Bruce A. FreemanAbstract:Fatty acid Nitroalkene derivatives (NO_2-FA) activate Nrf2-regulated antioxidant gene expression and inhibit NF-κB-dependent cytokine expression. To better define NO_2-FA structure-function relationships, a series of 22 new chemical entities (NCEs) containing an electrophilic Nitroalkene functional group were synthesized and screened for both Nrf2- and NF-κB activities using luciferase-based assays. The structural variables were acyl chain length (11 to 24 carbons) and position of the electrophilic Nitroalkene group. In luciferase-based reporter assays, Nrf2 was maximally activated by omega-12 Nitroalkene fatty acids while TNFα stimulated NF-κB-inhibition was maximal for omega-5 Nitroalkenes. The top pathway-modulating NO_2-FAs were a) evaluated for an ability to activate Nrf2-dependent signaling and inhibit NF-κB-dependent inflammatory responses of RAW264.7 cells and b) compared to electrophilic compounds in clinical development. These findings revealed that 8/9-nitro-eicos-8-enoic acid (NCE− 10 ) was collectively the most effective NCE and that both the α and ω acyl chain lengths influence Nitroalkene activation of Nrf2 and inhibition of NF-κB signaling. This insight will guide development of more effective non-natural homologs of endogenously-detectable fatty acid Nitroalkenes as anti-inflammatory and anti-fibrotic drug candidates.
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Electrophilic Nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses
Nature Publishing Group, 2018Co-Authors: Jorge Rodriguez-duarte, Francisco J Schopfer, Bruce A. Freeman, Nicholas K. H. Khoo, Rosina Dapueto, Germán Galliussi, Lucía Turell, Andrés Kamaid, Carlos Escande, Carlos BatthyanyAbstract:Abstract Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic Nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel Nitroalkenes derived from α-tocopherol aiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-Nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of Nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases
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inhibition of mycobacterium tuberculosis pkng by non catalytic rubredoxin domain specific modification reaction of an electrophilic nitro fatty acid with the fe s center
Free Radical Biology and Medicine, 2013Co-Authors: Martin Grana, Francisco J Schopfer, Carlos Batthyany, Ana Denicola, T Wagner, Bruce A. Freeman, Rosario DuranAbstract:PknG from Mycobacterium tuberculosis is a Ser/Thr protein kinase that regulates key metabolic processes within the bacterial cell as well as signaling pathways from the infected host cell. This multidomain protein has a conserved canonical kinase domain with N- and C-terminal flanking regions of unclear functional roles. The N-terminus harbors a rubredoxin-like domain (Rbx), a bacterial protein module characterized by an iron ion coordinated by four cysteine residues. Disruption of the Rbx-metal binding site by simultaneous mutations of all the key cysteine residues significantly impairs PknG activity. This encouraged us to evaluate the effect of a nitro-fatty acid (9- and 10-nitro-octadeca-9-cis-enoic acid; OA-NO2) on PknG activity. Fatty acid Nitroalkenes are electrophilic species produced during inflammation and metabolism that react with nucleophilic residues of target proteins (i.e., Cys and His), modulating protein function and subcellular distribution in a reversible manner. Here, we show that OA-NO2 inhibits kinase activity by covalently adducting PknG remote from the catalytic domain. Mass spectrometry-based analysis established that cysteines located at Rbx are the specific targets of the Nitroalkene. Cys-nitroalkylation is a Michael addition reaction typically reverted by thiols. However, the reversible OA-NO2-mediated nitroalkylation of the kinase results in an irreversible inhibition of PknG. Cys adduction by OA-NO2 induced iron release from the Rbx domain, revealing a new strategy for the specific inhibition of PknG. These results affirm the relevance of the Rbx domain as a target for PknG inhibition and support that electrophilic lipid reactions of Rbx-Cys may represent a new drug strategy for specific PknG inhibition.
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nitro fatty acid inhibition of neointima formation after endoluminal vessel injury
Circulation Research, 2009Co-Authors: Marsha P Cole, Francisco J Schopfer, Nicholas K. H. Khoo, Volker Rudolph, Tanja K Rudolph, Uche N. Motanya, Jeffrey W. Wertz, Steven R. Woodcock, Franca Golinbisello, Subhashini BolisettyAbstract:Rationale: Fatty acid Nitroalkenes are endogenously generated electrophilic byproducts of nitric oxide and nitrite-dependent oxidative inflammatory reactions. Existing evidence indicates Nitroalkenes support posttranslational protein modifications and transcriptional activation that promote the resolution of inflammation. Objective: The aim of this study was to assess whether in vivo administration of a synthetic Nitroalkene could elicit antiinflammatory actions in vivo using a murine model of vascular injury. Methods and Results: The in vivo administration (21 days) of nitro-oleic acid (OA-NO2) inhibited neointimal hyperplasia after wire injury of the femoral artery in a murine model (OA-NO2 treatment resulted in reduced intimal area and intima to media ratio versus vehicle- or oleic acid (OA)-treated animals, P<0.0001). Increased heme oxygenase (HO)-1 expression accounted for much of the vascular protection induced by OA-NO2 in both cultured aortic smooth muscle cells and in vivo. Inhibition of HO by Sn(IV)-protoporphyrin or HO-1 small interfering RNA reversed OA-NO2–induced inhibition of platelet-derived growth factor-stimulated rat aortic smooth muscle cell migration. The upregulation of HO-1 expression also accounted for the antistenotic actions of OA-NO2 in vivo, because inhibition of neointimal hyperplasia following femoral artery injury was abolished in HO-1 / mice (OA-NO2–treated wild-type versus HO-1 / mice, P0.016). Conclusions: In summary, electrophilic nitro-fatty acids induce salutary gene expression and cell functional responses that are manifested by a clinically significant outcome, inhibition of neointimal hyperplasia induced by arterial injury. (Circ Res. 2009;105:965-972.)
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detection and quantification of protein adduction by electrophilic fatty acids mitochondrial generation of fatty acid Nitroalkene derivatives
Free Radical Biology and Medicine, 2009Co-Authors: Francisco J Schopfer, Carlos Batthyany, Sergiy M Nadtochiy, Paul R S Baker, Gustavo Bonacci, Marsha P Cole, Volker Rudolph, Alison L Groeger, Tanja K Rudolph, Paul S BrookesAbstract:Nitroalkene fatty acid derivatives manifest a strong electrophilic nature, are clinically detectable, and induce multiple transcriptionally regulated anti-inflammatory responses. At present, the characterization and quantification of endogenous electrophilic lipids are compromised by their Michael addition with protein and small-molecule nucleophilic targets. Herein, we report a trans-nitroalkylation reaction of nitro-fatty acids with β-mercaptoethanol (BME) and apply this reaction to the unbiased identification and quantification of reaction with nucleophilic targets. Trans-nitroalkylation yields are maximal at pH 7 to 8 and occur with physiological concentrations of target nucleophiles. This reaction is also amenable to sensitive mass spectrometry-based quantification of electrophilic fatty acid–protein adducts upon electrophoretic resolution of proteins. In-gel trans-nitroalkylation reactions also permit the identification of protein targets without the bias and lack of sensitivity of current proteomic approaches. Using this approach, it was observed that fatty acid Nitroalkenes are rapidly metabolized in vivo by a Nitroalkene reductase activity and mitochondrial β-oxidation, yielding a variety of electrophilic and nonelectrophilic products that could be structurally characterized upon BME-based trans-nitroalkylation reaction. This strategy was applied to the detection and quantification of fatty acid nitration in mitochondria in response to oxidative inflammatory conditions induced by myocardial ischemia–reoxygenation.
Michael Rubin - One of the best experts on this subject based on the ideXlab platform.
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metal free ring expansion of indoles with Nitroalkenes a simple modular approach to 3 substituted 2 quinolones
RSC Advances, 2015Co-Authors: A V Aksenov, Alexander N Smirnov, N A Aksenov, I V Aksenova, Michael Rubin, Jonathon P MathenyAbstract:3-Substituted 2-quinolones are obtained via a novel metal-free transannulation reaction of 2-nitroolefins with 2-substituted indoles in polyphosphoric acid. This acid-mediated cascade transformation operates via the ANRORC (Addition of Nucleophile, Ring Opening, and Ring Closure) mechanism and can be used in combination with the Fisher indole synthesis to offer a practical three-component hetero-annulation approach to 2-quinolones from arylhydrazines, 2-Nitroalkenes, and acetophenone. An alternative entry to this chemistry employing the alkylation of electron-rich arenes and hetarenes with 1-(2-indolyl)-2-Nitroalkene has also been demonstrated.
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metal free transannulation reaction of indoles with nitrostyrenes a simple practical synthesis of 3 substituted 2 quinolones
Chemical Communications, 2013Co-Authors: A V Aksenov, Alexander N Smirnov, N A Aksenov, I V Aksenova, Liliya V Frolova, Alexander Kornienko, Igor V Magedov, Michael RubinAbstract:3-Substituted 2-quinolones are obtained via a novel, metal-free transannulation reaction of 2-substituted indoles with 2-Nitroalkenes in polyphosphoric acid. The reaction can be used in conjunction with the Fisher indole synthesis offering a practical three-component heteroannulation methodology to produce 2-quinolones from arylhydrazines, 2-Nitroalkenes and acetophenone.
Carlos Batthyany - One of the best experts on this subject based on the ideXlab platform.
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Electrophilic Nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses
Nature Publishing Group, 2018Co-Authors: Jorge Rodriguez-duarte, Francisco J Schopfer, Bruce A. Freeman, Nicholas K. H. Khoo, Rosina Dapueto, Germán Galliussi, Lucía Turell, Andrés Kamaid, Carlos Escande, Carlos BatthyanyAbstract:Abstract Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic Nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel Nitroalkenes derived from α-tocopherol aiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-Nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of Nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases
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inhibition of mycobacterium tuberculosis pkng by non catalytic rubredoxin domain specific modification reaction of an electrophilic nitro fatty acid with the fe s center
Free Radical Biology and Medicine, 2013Co-Authors: Martin Grana, Francisco J Schopfer, Carlos Batthyany, Ana Denicola, T Wagner, Bruce A. Freeman, Rosario DuranAbstract:PknG from Mycobacterium tuberculosis is a Ser/Thr protein kinase that regulates key metabolic processes within the bacterial cell as well as signaling pathways from the infected host cell. This multidomain protein has a conserved canonical kinase domain with N- and C-terminal flanking regions of unclear functional roles. The N-terminus harbors a rubredoxin-like domain (Rbx), a bacterial protein module characterized by an iron ion coordinated by four cysteine residues. Disruption of the Rbx-metal binding site by simultaneous mutations of all the key cysteine residues significantly impairs PknG activity. This encouraged us to evaluate the effect of a nitro-fatty acid (9- and 10-nitro-octadeca-9-cis-enoic acid; OA-NO2) on PknG activity. Fatty acid Nitroalkenes are electrophilic species produced during inflammation and metabolism that react with nucleophilic residues of target proteins (i.e., Cys and His), modulating protein function and subcellular distribution in a reversible manner. Here, we show that OA-NO2 inhibits kinase activity by covalently adducting PknG remote from the catalytic domain. Mass spectrometry-based analysis established that cysteines located at Rbx are the specific targets of the Nitroalkene. Cys-nitroalkylation is a Michael addition reaction typically reverted by thiols. However, the reversible OA-NO2-mediated nitroalkylation of the kinase results in an irreversible inhibition of PknG. Cys adduction by OA-NO2 induced iron release from the Rbx domain, revealing a new strategy for the specific inhibition of PknG. These results affirm the relevance of the Rbx domain as a target for PknG inhibition and support that electrophilic lipid reactions of Rbx-Cys may represent a new drug strategy for specific PknG inhibition.
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detection and quantification of protein adduction by electrophilic fatty acids mitochondrial generation of fatty acid Nitroalkene derivatives
Free Radical Biology and Medicine, 2009Co-Authors: Francisco J Schopfer, Carlos Batthyany, Sergiy M Nadtochiy, Paul R S Baker, Gustavo Bonacci, Marsha P Cole, Volker Rudolph, Alison L Groeger, Tanja K Rudolph, Paul S BrookesAbstract:Nitroalkene fatty acid derivatives manifest a strong electrophilic nature, are clinically detectable, and induce multiple transcriptionally regulated anti-inflammatory responses. At present, the characterization and quantification of endogenous electrophilic lipids are compromised by their Michael addition with protein and small-molecule nucleophilic targets. Herein, we report a trans-nitroalkylation reaction of nitro-fatty acids with β-mercaptoethanol (BME) and apply this reaction to the unbiased identification and quantification of reaction with nucleophilic targets. Trans-nitroalkylation yields are maximal at pH 7 to 8 and occur with physiological concentrations of target nucleophiles. This reaction is also amenable to sensitive mass spectrometry-based quantification of electrophilic fatty acid–protein adducts upon electrophoretic resolution of proteins. In-gel trans-nitroalkylation reactions also permit the identification of protein targets without the bias and lack of sensitivity of current proteomic approaches. Using this approach, it was observed that fatty acid Nitroalkenes are rapidly metabolized in vivo by a Nitroalkene reductase activity and mitochondrial β-oxidation, yielding a variety of electrophilic and nonelectrophilic products that could be structurally characterized upon BME-based trans-nitroalkylation reaction. This strategy was applied to the detection and quantification of fatty acid nitration in mitochondria in response to oxidative inflammatory conditions induced by myocardial ischemia–reoxygenation.
Bruce A. Freeman - One of the best experts on this subject based on the ideXlab platform.
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Electrophilic fatty acid Nitroalkenes regulate Nrf2 and NF-κB signaling:A medicinal chemistry investigation of structure-function relationships
Scientific Reports, 2018Co-Authors: Nicholas K. H. Khoo, Francisco J Schopfer, Sonia R. Salvatore, Bruce A. FreemanAbstract:Fatty acid Nitroalkene derivatives (NO_2-FA) activate Nrf2-regulated antioxidant gene expression and inhibit NF-κB-dependent cytokine expression. To better define NO_2-FA structure-function relationships, a series of 22 new chemical entities (NCEs) containing an electrophilic Nitroalkene functional group were synthesized and screened for both Nrf2- and NF-κB activities using luciferase-based assays. The structural variables were acyl chain length (11 to 24 carbons) and position of the electrophilic Nitroalkene group. In luciferase-based reporter assays, Nrf2 was maximally activated by omega-12 Nitroalkene fatty acids while TNFα stimulated NF-κB-inhibition was maximal for omega-5 Nitroalkenes. The top pathway-modulating NO_2-FAs were a) evaluated for an ability to activate Nrf2-dependent signaling and inhibit NF-κB-dependent inflammatory responses of RAW264.7 cells and b) compared to electrophilic compounds in clinical development. These findings revealed that 8/9-nitro-eicos-8-enoic acid (NCE− 10 ) was collectively the most effective NCE and that both the α and ω acyl chain lengths influence Nitroalkene activation of Nrf2 and inhibition of NF-κB signaling. This insight will guide development of more effective non-natural homologs of endogenously-detectable fatty acid Nitroalkenes as anti-inflammatory and anti-fibrotic drug candidates.
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Electrophilic Nitroalkene-tocopherol derivatives: synthesis, physicochemical characterization and evaluation of anti-inflammatory signaling responses
Nature Publishing Group, 2018Co-Authors: Jorge Rodriguez-duarte, Francisco J Schopfer, Bruce A. Freeman, Nicholas K. H. Khoo, Rosina Dapueto, Germán Galliussi, Lucía Turell, Andrés Kamaid, Carlos Escande, Carlos BatthyanyAbstract:Abstract Inflammation plays a major role in the onset and development of chronic non-communicable diseases like obesity, cardiovascular diseases and cancer. Combined, these diseases represent the most common causes of death worldwide, thus development of novel pharmacological approaches is crucial. Electrophilic Nitroalkenes derived from fatty acids are formed endogenously and exert anti-inflammatory actions by the modification of proteins involved in inflammation signaling cascades. We have developed novel Nitroalkenes derived from α-tocopherol aiming to increase its salutary actions by adding anti-inflammatory properties to a well-known nutraceutical. We synthesized and characterized an α-tocopherol-Nitroalkene (NATOH) and two hydrosoluble analogues derived from Trolox (NATxME and NATx0). We analyzed the kinetics of the Michael addition reaction of these compounds with thiols in micellar systems aiming to understand the effect of hydrophobic partition on the reactivity of Nitroalkenes. We studied NATxME in vitro showing it exerts non-conventional anti-inflammatory responses by inducing Nrf2-Keap1-dependent gene expression and inhibiting the secretion of NF-κB dependent pro-inflammatory cytokines. NATxME was also effective in vivo, inhibiting neutrophil recruitment in a zebrafish model of inflammation. This work lays the foundation for the rational design of a new therapeutic strategy for the prevention and treatment of metabolic and inflammation-related diseases
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inhibition of mycobacterium tuberculosis pkng by non catalytic rubredoxin domain specific modification reaction of an electrophilic nitro fatty acid with the fe s center
Free Radical Biology and Medicine, 2013Co-Authors: Martin Grana, Francisco J Schopfer, Carlos Batthyany, Ana Denicola, T Wagner, Bruce A. Freeman, Rosario DuranAbstract:PknG from Mycobacterium tuberculosis is a Ser/Thr protein kinase that regulates key metabolic processes within the bacterial cell as well as signaling pathways from the infected host cell. This multidomain protein has a conserved canonical kinase domain with N- and C-terminal flanking regions of unclear functional roles. The N-terminus harbors a rubredoxin-like domain (Rbx), a bacterial protein module characterized by an iron ion coordinated by four cysteine residues. Disruption of the Rbx-metal binding site by simultaneous mutations of all the key cysteine residues significantly impairs PknG activity. This encouraged us to evaluate the effect of a nitro-fatty acid (9- and 10-nitro-octadeca-9-cis-enoic acid; OA-NO2) on PknG activity. Fatty acid Nitroalkenes are electrophilic species produced during inflammation and metabolism that react with nucleophilic residues of target proteins (i.e., Cys and His), modulating protein function and subcellular distribution in a reversible manner. Here, we show that OA-NO2 inhibits kinase activity by covalently adducting PknG remote from the catalytic domain. Mass spectrometry-based analysis established that cysteines located at Rbx are the specific targets of the Nitroalkene. Cys-nitroalkylation is a Michael addition reaction typically reverted by thiols. However, the reversible OA-NO2-mediated nitroalkylation of the kinase results in an irreversible inhibition of PknG. Cys adduction by OA-NO2 induced iron release from the Rbx domain, revealing a new strategy for the specific inhibition of PknG. These results affirm the relevance of the Rbx domain as a target for PknG inhibition and support that electrophilic lipid reactions of Rbx-Cys may represent a new drug strategy for specific PknG inhibition.
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Nitroalkenes suppress lipopolysaccharide induced signal transducer and activator of transcription signaling in macrophages a critical role of mitogen activated protein kinase phosphatase 1
Endocrinology, 2008Co-Authors: Francisco J Schopfer, Bruce A. Freeman, Paul R S Baker, Tomonaga Ichikawa, Jifeng Zhang, Kai Chen, Yuqing E ChenAbstract:Nitration products of unsaturated fatty acids are formed via NO-dependent oxidative reactions and appear to be a new class of endogenous antiinflammatory mediators. Nitroalkene derivatives of nitrated linoleic acid (LNO2) and nitrated oleic acid (OA-NO2) alleviate inflammatory responses in macrophages, but the underlying mechanisms remain to be fully defined. Herein we report that LNO2 and OA-NO2 suppress proinflammatory signal transducer and activator of transcription (STAT) signaling in macrophages. In RAW264.7 cells, a murine macrophage cell line, LNO2 and OA-NO2 inhibited the lipopolysaccharide (LPS)-induced STAT1 phosphorylation and the STAT1-dependent transcriptional activity, thereby suppressing expression of its target gene such as iNOS and MCP-1. The Nitroalkene-mediated inhibition of STAT1 activity was not affected by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (a NO scavenger), GW9662 (a peroxisome proliferator-activated receptor-γ-specific antagonist) or glutathione (an antioxidant), suggesting an underlying mechanism independent of NO, peroxisome proliferator-activated receptor-γ, or thio-nitralkylation. In contrast, LNO2 or OA-NO2 alone up-regulated both mRNA and protein levels of MAPK phosphatase 1 (MKP-1) and strongly augmented the LPS-induced MKP-1 protein expression. Knockdown of MKP-1 by MKP-1 small interfering RNA enhanced the LPS-induced STAT1 phosphorylation, suggesting that MKP-1 acts as a negative regulator for LPS-induced STAT signaling. In addition, the Nitroalkene-mediated inhibitory effects on STAT1 phosphorylation, iNOS expression, and MCP-1 secretion were also largely attenuated by the MKP-1 small interfering RNA approach. Taken together, our data demonstrate that Nitroalkenes inhibit proinflammatory STAT signaling through inducting MKP-1 in macrophages.
Rosario Duran - One of the best experts on this subject based on the ideXlab platform.
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inhibition of mycobacterium tuberculosis pkng by non catalytic rubredoxin domain specific modification reaction of an electrophilic nitro fatty acid with the fe s center
Free Radical Biology and Medicine, 2013Co-Authors: Martin Grana, Francisco J Schopfer, Carlos Batthyany, Ana Denicola, T Wagner, Bruce A. Freeman, Rosario DuranAbstract:PknG from Mycobacterium tuberculosis is a Ser/Thr protein kinase that regulates key metabolic processes within the bacterial cell as well as signaling pathways from the infected host cell. This multidomain protein has a conserved canonical kinase domain with N- and C-terminal flanking regions of unclear functional roles. The N-terminus harbors a rubredoxin-like domain (Rbx), a bacterial protein module characterized by an iron ion coordinated by four cysteine residues. Disruption of the Rbx-metal binding site by simultaneous mutations of all the key cysteine residues significantly impairs PknG activity. This encouraged us to evaluate the effect of a nitro-fatty acid (9- and 10-nitro-octadeca-9-cis-enoic acid; OA-NO2) on PknG activity. Fatty acid Nitroalkenes are electrophilic species produced during inflammation and metabolism that react with nucleophilic residues of target proteins (i.e., Cys and His), modulating protein function and subcellular distribution in a reversible manner. Here, we show that OA-NO2 inhibits kinase activity by covalently adducting PknG remote from the catalytic domain. Mass spectrometry-based analysis established that cysteines located at Rbx are the specific targets of the Nitroalkene. Cys-nitroalkylation is a Michael addition reaction typically reverted by thiols. However, the reversible OA-NO2-mediated nitroalkylation of the kinase results in an irreversible inhibition of PknG. Cys adduction by OA-NO2 induced iron release from the Rbx domain, revealing a new strategy for the specific inhibition of PknG. These results affirm the relevance of the Rbx domain as a target for PknG inhibition and support that electrophilic lipid reactions of Rbx-Cys may represent a new drug strategy for specific PknG inhibition.