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Electrophilic characteristics and aqueous behavior of fatty acid nitroalkenes
- Source :
- Redox Biology, Redox Biology, Vol 38, Iss, Pp 101756-(2021)
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
Abstract
- Fatty acid nitroalkenes (NO2-FA) are endogenously-generated products of the reaction of metabolic and inflammatory-derived nitrogen dioxide (.NO2) with unsaturated fatty acids. These species mediate signaling actions and induce adaptive responses in preclinical models of inflammatory and metabolic diseases. The nitroalkene substituent possesses an electrophilic nature, resulting in rapid and reversible reactions with biological nucleophiles such as cysteine, thus supporting post-translational modifications (PTM) of proteins having susceptible nucleophilic centers. These reactions contribute to enzyme regulation, modulation of inflammation and cell proliferation and the regulation of gene expression responses. Herein, focus is placed on the reduction-oxidation (redox) characteristics and stability of specific NO2-FA regioisomers having biological and clinical relevance; nitro-oleic acid (NO2-OA), bis-allylic nitro-linoleic acid (NO2-LA) and the conjugated diene-containing nitro-conjugated linoleic acid (NO2-cLA). Cyclic and alternating-current voltammetry and chronopotentiometry were used to the study of reduction potentials of these NO2-FA. R–NO2 reduction was observed around −0.8 V (vs. Ag/AgCl/3 M KCl) and is related to relative NO2-FA electrophilicity. This reduction process could be utilized for the evaluation of NO2-FA stability in aqueous milieu, shown herein to be pH dependent. In addition, electron paramagnetic resonance (EPR) spectroscopy was used to define the stability of the nitroalkene moiety under aqueous conditions, specifically under conditions where nitric oxide (.NO) release could be detected. The experimental data were supported by density functional theory calculations using 6–311++G (d,p) basis set and B3LYP functional. Based on experimental and computational approaches, the relative electrophilicities of these NO2-FA are NO2-cLA >> NO2-LA > NO2-OA. Micellarization and vesiculation largely define these biophysical characteristics in aqueous, nucleophile-free conditions. At concentrations below the critical micellar concentration (CMC), monomeric NO2-FA predominate, while at greater concentrations a micellar phase consisting of self-assembled lipid structures predominates. The CMC, determined by dynamic light scattering in 0.1 M phosphate buffer (pH 7.4) at 25 °C, was 6.9 (NO2-LA) 10.6 (NO2-OA) and 42.3 μM (NO2-cLA), respectively. In aggregate, this study provides new insight into the biophysical properties of NO2-FA that are important for better understanding the cell signaling and pharmacological potential of this class of mediators.<br />Highlights • Nitro-fatty acids (NO2-FA) are electrophilic mediators of redox-regulated signaling reactions. • The relative electrophilicity of 18 carbon chain length NO2-FA is NO2-cLA » NO2-LA > NO2-OA. • Critical micellar concentrations at pH 7.4 were 10.6, 6.9 and 42.3 μM for NO2-OA, NO2-LA and NO2-cLA, respectively. • Nitrogen dioxide (.NO2) rapidly reacts with unsaturated FA and yields more stable bioactive NO2-FA byproducts.
- Subjects :
- 0301 basic medicine
inorganic chemicals
Linoleic acid
Clinical Biochemistry
Substituent
Alkenes
Nitroalkene
Biochemistry
Redox
complex mixtures
Reversible reaction
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Free radical
lcsh:QH301-705.5
chemistry.chemical_classification
lcsh:R5-920
Aqueous solution
Chemistry
Organic Chemistry
Fatty Acids
Fatty acid
Nitric oxide
respiratory system
Nitro Compounds
Combinatorial chemistry
respiratory tract diseases
Nitro-fatty acid
030104 developmental biology
lcsh:Biology (General)
Electrophile
lcsh:Medicine (General)
Oxidation-Reduction
030217 neurology & neurosurgery
Cysteine
Research Paper
Micelle
Subjects
Details
- Language :
- English
- ISSN :
- 22132317
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Redox Biology
- Accession number :
- edsair.doi.dedup.....4ac4825c9e07b20cb83112bee25bfd8d