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Endogenous Generation and Signaling Actions of Omega-3 Fatty Acid Electrophilic Derivatives.

Cipollina C - Biomed Res Int (2015)

Bottom Line: Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects.Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop.The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Fondazione Ri.MED, Palermo, Italy ; Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche, 90146 Palermo, Italy.

ABSTRACT
Dietary omega-3 polyunsaturated fatty acids (PUFAs) are beneficial for a number of conditions ranging from cardiovascular disease to chronic airways disorders, neurodegeneration, and cancer. Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects. Electrophilic oxo-derivatives of omega-3 PUFAs represent a class of oxidized derivatives that can be generated via enzymatic and nonenzymatic pathways. Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop. Endogenous generation of electrophilic oxo-derivatives of omega-3 PUFAs has been observed in in vitro and ex vivo human models and dietary supplementation of omega-3 PUFAs has been reported to increase their formation. Due to the presence of an α,β-unsaturated ketone moiety, these compounds covalently and reversibly react with nucleophilic residues on target proteins triggering the activation of cytoprotective pathways, including the Nrf2 antioxidant response, the heat shock response, and the peroxisome proliferator activated receptor γ (PPARγ) and suppressing the NF-κB proinflammatory pathway. The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

No MeSH data available.


Related in: MedlinePlus

Reaction scheme of electrophilic lipid derivatives. Electrophilic α,β-unsaturated ketone moieties react with nucleophilic residues on target proteins (thiolates of cysteines and amino groups of histidine and lysine) via Michael reaction. In the case of bifunctional electrophiles, the aldehyde group reacts with primary amines of lysine generating Schiff base adducts.
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fig1: Reaction scheme of electrophilic lipid derivatives. Electrophilic α,β-unsaturated ketone moieties react with nucleophilic residues on target proteins (thiolates of cysteines and amino groups of histidine and lysine) via Michael reaction. In the case of bifunctional electrophiles, the aldehyde group reacts with primary amines of lysine generating Schiff base adducts.

Mentions: Enzymatic and nonenzymatic oxidation of omega-3 PUFAs generates a broad range of oxygenated species containing electrophilic α,β-unsaturated ketone moieties. The presence of a double bond conjugated to a ketogroup renders the β-carbon electron poor and is therefore susceptible to nucleophilic attack. Reaction of α,β-unsaturated ketones with nucleophiles occurs via Michael addition during which the electron-poor β-carbon accepts the pair of electrons of the electron-rich nucleophile forming a covalent bond (Figure 1). The chemistry governing the reaction between electrophiles and nucleophiles is described by the hard/soft acid-base theory [19] that provides a framework for understanding the reactivity of these species in which soft (polarizable) electrophiles preferentially react with soft nucleophiles while hard (nonpolarizable) electrophiles favorably react with hard nucleophiles. The “electrophilicity index” was later introduced by Parr et al. to better describe the chemical properties of electrophilic species [20]. The electrophilicity index combines softness and chemical potential and can be used to predict the reactivity of an electrophile and to anticipate its biological activity and potential toxicity [21, 22]. For example, several mutagenic compounds present a high electrophilicity index and are hard electrophiles thus reacting more favorably with hard nucleophilic groups found in purine and pyrimidine bases leading to irreversible modification of DNA [23]. In contrast, α,β-unsaturated ketones are soft electrophiles that preferentially react with soft nucleophiles, including cysteine thiols and to a lesser extent primary and secondary amines of lysine and histidine residues, respectively. More specifically, the thiolate anion form of cysteine is the preferred target for α,β-unsaturated ketones [24, 25]. In this regard, the pKa of a cysteine is defined as the pH at which 50% is in an ionized state (deprotonated) and is between 8 and 9 for most biologically relevant thiols, close to the physiological pH range. This means that small changes of cysteine pKa that can be caused by conformational modifications, changes of intracellular distribution, or protein-lipid interaction will significantly affect thiolate levels. This modulation of cysteine reactivity provides a framework for fine-tuning of posttranslational modifications within physiological pH ranges [25]. In addition to cysteine pKa, the reactivity of a given electrophile towards a nucleophilic residue will depend on structural factors including the accessibility of the nucleophilic site and the presence of a microenvironment that stabilizes protein-lipid interaction thus favoring Michael addition. Polar and hydrophobic interactions between the electrophilic fatty acid and exposed amino acids are crucial for the right positioning of the reactive carbon in order for the Michael addition to occur. In this respect, extensive structural investigations on the covalent binding between electrophilic lipids (oxo-fatty acids and nitroalkenes) and Cys-285 within the ligand binding pocket of the peroxisome proliferator-activated receptor γ (PPARγ) provided important mechanistic information [26–28]. In this particular case, the fatty acid is bound to the receptor so that the carboxylate and the electron-withdrawing groups (either nitro- or keto-) interact with polar residues in the binding pocket while the aliphatic chain is stabilized through hydrophobic interactions [26–28]. Moreover, it has been proposed that polar side chains close to the electrophilic carbon may enhance the electron-withdrawing effect of the ketogroup thus promoting Michael addition reactions [26].


Endogenous Generation and Signaling Actions of Omega-3 Fatty Acid Electrophilic Derivatives.

Cipollina C - Biomed Res Int (2015)

Reaction scheme of electrophilic lipid derivatives. Electrophilic α,β-unsaturated ketone moieties react with nucleophilic residues on target proteins (thiolates of cysteines and amino groups of histidine and lysine) via Michael reaction. In the case of bifunctional electrophiles, the aldehyde group reacts with primary amines of lysine generating Schiff base adducts.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538325&req=5

fig1: Reaction scheme of electrophilic lipid derivatives. Electrophilic α,β-unsaturated ketone moieties react with nucleophilic residues on target proteins (thiolates of cysteines and amino groups of histidine and lysine) via Michael reaction. In the case of bifunctional electrophiles, the aldehyde group reacts with primary amines of lysine generating Schiff base adducts.
Mentions: Enzymatic and nonenzymatic oxidation of omega-3 PUFAs generates a broad range of oxygenated species containing electrophilic α,β-unsaturated ketone moieties. The presence of a double bond conjugated to a ketogroup renders the β-carbon electron poor and is therefore susceptible to nucleophilic attack. Reaction of α,β-unsaturated ketones with nucleophiles occurs via Michael addition during which the electron-poor β-carbon accepts the pair of electrons of the electron-rich nucleophile forming a covalent bond (Figure 1). The chemistry governing the reaction between electrophiles and nucleophiles is described by the hard/soft acid-base theory [19] that provides a framework for understanding the reactivity of these species in which soft (polarizable) electrophiles preferentially react with soft nucleophiles while hard (nonpolarizable) electrophiles favorably react with hard nucleophiles. The “electrophilicity index” was later introduced by Parr et al. to better describe the chemical properties of electrophilic species [20]. The electrophilicity index combines softness and chemical potential and can be used to predict the reactivity of an electrophile and to anticipate its biological activity and potential toxicity [21, 22]. For example, several mutagenic compounds present a high electrophilicity index and are hard electrophiles thus reacting more favorably with hard nucleophilic groups found in purine and pyrimidine bases leading to irreversible modification of DNA [23]. In contrast, α,β-unsaturated ketones are soft electrophiles that preferentially react with soft nucleophiles, including cysteine thiols and to a lesser extent primary and secondary amines of lysine and histidine residues, respectively. More specifically, the thiolate anion form of cysteine is the preferred target for α,β-unsaturated ketones [24, 25]. In this regard, the pKa of a cysteine is defined as the pH at which 50% is in an ionized state (deprotonated) and is between 8 and 9 for most biologically relevant thiols, close to the physiological pH range. This means that small changes of cysteine pKa that can be caused by conformational modifications, changes of intracellular distribution, or protein-lipid interaction will significantly affect thiolate levels. This modulation of cysteine reactivity provides a framework for fine-tuning of posttranslational modifications within physiological pH ranges [25]. In addition to cysteine pKa, the reactivity of a given electrophile towards a nucleophilic residue will depend on structural factors including the accessibility of the nucleophilic site and the presence of a microenvironment that stabilizes protein-lipid interaction thus favoring Michael addition. Polar and hydrophobic interactions between the electrophilic fatty acid and exposed amino acids are crucial for the right positioning of the reactive carbon in order for the Michael addition to occur. In this respect, extensive structural investigations on the covalent binding between electrophilic lipids (oxo-fatty acids and nitroalkenes) and Cys-285 within the ligand binding pocket of the peroxisome proliferator-activated receptor γ (PPARγ) provided important mechanistic information [26–28]. In this particular case, the fatty acid is bound to the receptor so that the carboxylate and the electron-withdrawing groups (either nitro- or keto-) interact with polar residues in the binding pocket while the aliphatic chain is stabilized through hydrophobic interactions [26–28]. Moreover, it has been proposed that polar side chains close to the electrophilic carbon may enhance the electron-withdrawing effect of the ketogroup thus promoting Michael addition reactions [26].

Bottom Line: Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects.Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop.The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Fondazione Ri.MED, Palermo, Italy ; Istituto di Biomedicina e Immunologia Molecolare (IBIM), Consiglio Nazionale delle Ricerche, 90146 Palermo, Italy.

ABSTRACT
Dietary omega-3 polyunsaturated fatty acids (PUFAs) are beneficial for a number of conditions ranging from cardiovascular disease to chronic airways disorders, neurodegeneration, and cancer. Growing evidence has shown that bioactive oxygenated derivatives are responsible for transducing these salutary effects. Electrophilic oxo-derivatives of omega-3 PUFAs represent a class of oxidized derivatives that can be generated via enzymatic and nonenzymatic pathways. Inflammation and oxidative stress favor the formation of these signaling species to promote the resolution of inflammation within a fine autoregulatory loop. Endogenous generation of electrophilic oxo-derivatives of omega-3 PUFAs has been observed in in vitro and ex vivo human models and dietary supplementation of omega-3 PUFAs has been reported to increase their formation. Due to the presence of an α,β-unsaturated ketone moiety, these compounds covalently and reversibly react with nucleophilic residues on target proteins triggering the activation of cytoprotective pathways, including the Nrf2 antioxidant response, the heat shock response, and the peroxisome proliferator activated receptor γ (PPARγ) and suppressing the NF-κB proinflammatory pathway. The endogenous nature of electrophilic oxo-derivatives of omega-3 PUFAs combined with their ability to simultaneously activate multiple cytoprotective pathways has made these compounds attractive for the development of new therapies for the treatment of chronic disorders and acute events characterized by inflammation and oxidative stress.

No MeSH data available.


Related in: MedlinePlus