Nitro Fatty Acids (NO2-FAs): An Emerging Class of Bioactive Fatty Acids

Abstract

Unsaturated nitro fatty acids (NO2-FAs) constitute a category of molecules that may be formed endogenously by the reaction of unsaturated fatty acids (UFAs) with secondary species of nitrogen monoxide and nitrite anions. The warhead of NO2-FAs is a nitroalkene moiety, which is a potent Michael acceptor and can undergo nucleophilic attack from thiol groups of biologically relevant proteins, showcasing the value of these molecules regarding their therapeutic potential against many diseases. In general, NO2-FAs inhibit nuclear factorκ-B (NF-κB), and simultaneously they activate nuclear factor (erythroid derived)-like 2 (Nrf2), which activates an antioxidant signaling pathway. NO2-FAs can be synthesized not only endogenously in the organism, but in a synthetic laboratory as well, either by a step-by-step synthesis or by a direct nitration of UFAs. The step-by-step synthesis requires specific precursor compounds and is in position to afford the desired NO2-FAs with a certain position of the nitro group. On the contrary, the direct nitration of UFAs is not a selective methodology; thus, it affords a mixture of all possible nitro isomers.

Identifying transdiagnostic biological subtypes across schizophrenia, bipolar disorder, and major depressive disorder based on lipidomics profiles

“…10-Nitro-9Z,12Z-octadecadienoic acid (nitrolinoleic acid, LNO 2 ) is rich in human plasma and red cell membranes. It acts as a lipid-derived mediator in activating antioxidant signalling pathways ( Kalyanaraman, 2004 ; Koutoulogenis and Kokotos, 2021 ). LNO 2 also exhibits robust cell signalling activities as an anti-inflammatory ( Coles et al, 2002 ; Schopfer et al, 2005 ; Wright et al, 2006 ; Koutoulogenis and Kokotos, 2021 ).…”

“…It acts as a lipid-derived mediator in activating antioxidant signalling pathways ( Kalyanaraman, 2004 ; Koutoulogenis and Kokotos, 2021 ). LNO 2 also exhibits robust cell signalling activities as an anti-inflammatory ( Coles et al, 2002 ; Schopfer et al, 2005 ; Wright et al, 2006 ; Koutoulogenis and Kokotos, 2021 ). In this study, decreased plasma LNO 2 might indicate the vulnerable anti-inflammatory status of psychiatric patients.…”

Michael Acceptors as Anti-Cancer Compounds: Coincidence or Causality?

“…Daunorubicin, which is naturally produced by Streptomyces peucetius [134], paved the way for the development of The NO 2 -FAs moiety, characterized by a nitroalkene structure, acts as a potent MA that can react with thiol-containing residues in biologically relevant proteins. This reactivity enhances the therapeutic potential of NO 2 -FAs [128].…”

Nitro-fatty acids: mechanisms of action, roles in metabolic diseases, and therapeutics

“…In disease animal models, NO 2 -FAs are involved in multiple protective mechanisms related to anti-atherosclerosis (Rudolph et al 2010a, b), blood-pressure lowering (Kansanen et al 2017), anti-inflammatory (Villacorta et al 2018), and anti-insulin resistance (Khoo et al 2019) effects, and are involved in the regulation of glycolipid metabolism (Arbeeny et al 2019). The electrophilic properties of NO 2 -FAs enable NO 2 -FAs to undergo reversible Michael addition reactions with cysteine and histidine residues, resulting in the post-translational modification (PTM) of proteins (Koutoulogenis & Kokotos 2021). The NO 2 -FA-induced PTM of signaling proteins can lead to modifications in the protein structure and function, triggering a cascade of downstream signaling events, including gene expression, enzyme activity, and regulation of cellular processes (Grippo et al 2021).…”