Discovery of Kyn-CKA as a novel redox active product of Tryptophan Metabolism. Under steady-state conditions, >90% of tryptophan (Trp) catabolism occurs via the kynurenine (Kyn) pathway. Altered Kyn metabolism is observed in aging, cardiovascular disease, organ injury, cancer, and transplantation, where it often is a strong predictor of outcome. However, the mechanisms behind the effects of altered systemic and local Kyn metabolism are poorly defined. Using untargeted and targeted mass spectrometry techniques we discovered the endogenous formation of the electrophilic mediator kynurenine-carboxyketoalkene (Kyn CKA) in humans and mice. Kyn-CKA promotes Nrf2-depedent signaling, inhibits NF-kB pathways, attenuates inflammatory responses in endotoxin-challenged mice and inhibits pulmonary vaso-occlusion in a mouse model of sickle cell disease. These findings were published in Science Advances in 2022 and were instrumental for securing two large 5-year NIH awards (R01, R35).

  1. Carreño M et al, Vitturi DA.Sci Adv. 2022; 8(26): eabm9138. PMCID: PMC9242454.

Thiol-Reactive Electrophiles as Endogenous Mediators in vivo: The reaction of ●NO2 with unsaturated fatty acids such as conjugated linoleic acid (CLA), results in the formation of electrophilic nitrated fatty acids (NFAs). We identified CLA as the main substrate for inflammatory nitration in vivo and NO2-CLA as both a potent inducer of Nrf2-dependent responses and an inhibitor of NF-kB-dependent pathways (a). This report is highly cited and received 6.86 times more citations than the field average. The importance of this finding was highlighted in (b) where we identified NO2-CLA as a potential determinant of survival and neurological outcome in out-of-hospital cardiac arrest patients.

  1. Villacorta L et al, Vitturi DA. Redox Biol. 2018; 15:522-531.PMCID: PMC5881417.
  2. Vitturi DAet al. Redox Biol. 2020; 32:101463. PMCID: PMC7033352.


Chemical Basis for the Formation and Biological Actions of Nitric Oxide-Derived Electrophiles: Many of the physiological actions of Nitric Oxide (●NO) are independent of cGMP signaling. In this context, ●NO signaling is governed by the generation of secondary species such as S-nitrosothiols and nitrated fatty acids (NFAs). Nitrite is at the crux of these pathways. In (a), we discovered that nitrite is incorporated into both nitrated and nitrosated products under neutral pH and in the absence of metal catalysis via the formation of symmetrical nitrous anhydride (symN2O3). These observations, which were recapitulated in cell systems and in mouse models of inflammation, were the first demonstration of the formation of symN2O3 in vivo. This publication has been extremely highly cited, receiving 8.52 times more citations than the average of the field. In line with our interest in understanding signaling events through chemical reactivity, in (b) we defined the mechanism behind the reaction between NO2‑CLA and thiol residues, a central tenet of NFA biological actions. In (c), we elucidated the intricate effects of exogenous NFA on thiol homeostasis, revealing a previously unappreciated dissociation between the effects of oxidative stress and Nrf2 induction on GSH:GSSG ratios. Our contributions to this field are summarized and contextualized in a recent review published in Redox Biochemistry and Chemistry, as part of a special issue celebrating the 25th Anniversary of the NO Nobel Prize.

  1. Vitturi DAet al. Nat Chem Biol. 2015;11(7):504-10. PMCID: PMC4472503.
  2.  Turell L and Vitturi DA et al. J Biol Chem. 2017; 292(4):1145-1159. PMCID: PMC5270462.
  3. Jobbagy S, Vitturi DA, et al. Redox Biol. 2019; 21:101050. PMCID: PMC6348771.
  4. Moller MN and Vitturi DA. Redox Biochem Chem. 2024; 8:100026. PMCID: PMC11218869.


NO2− incorporation into NO2-CLA and GSNO is associated with symN2O3 formation. (a) Scheme illustrating the asymmetrical (1) and symmetrical (2) conformations of N2O3. Arrows indicate alternative bond cleavage patterns. Whereas asymN2O3 homolysis produces a unique set of products (1a, 1b), alternative cleavage of the O-N-O bonds in symN2O3 can be evidenced by isotopic labeling (blue and red represent 14N and 16O, respectively; dark blue and green are 15N and 18O). (b) Distribution of NO2-CLA isotopologues versus 15N18O2− concentration in the presence of 25 μM MNO and 20 μM CLA. (c) Isotopic GSNO distribution versus 15N18O2− in the presence of 2.5 μM MNO and 20 μM GSH. Data for b,c are mean ± s.d. (n = 4). Error bars are not distinguishable as they overlap with data points. Figure 4 from: Vitturi et al. Nat Chem Biol 11, 504–510 (2015).

 Summary of the main reactions leading to N2O3 formation and consumption under physiological conditions. 1: k1 = 13.4 M−1s−1; 2: pKa = 3.2; 3: k3 = 530 s−1; 4: k4 > 6 × 107 M−1s−1; 5: k5 = 8.1 × 104 s−1, k-5 = 1.1 × 109 M−1s−1; 6: KP6 = 1.5; 7: KP7 = 3.6; 8: KP8 = 3.2; 9: k9 = 2.9 × 106 M−2s−1; 10: CLA nitration follows a complex mechanism. Figure 1 from: Moller and Vitturi. Redox Biochem Chem. 2024 Jun; 8: 100026.