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.
Formation, metabolism and cell signaling actions of tryptophan catabolism-derived electrophiles. Our laboratory recently received an R35 grant from the National Institute of General Medical Sciences (R35GM152083) to test the hypothesis that tryptophan (Trp) catabolism yields novel bioactive products that adaptively modulate cellular responses via redox-dependent mechanisms. We are characterizing the mechanisms that regulate the formation and levels of Trp-derived electrophiles in the kynurenine pathway as well as working on identifying novel enzymes capable of catalyzing Kyn-CKA formation. The effects of Trp-derived electrophiles on cellular and tissue bioenergetic metabolism will be characterized, as well as the role of dietary Trp and the gut microbiome in regulating Trp-derived electrophile levels. We expect our research provide a solid biochemical foundation that will enable the development of clinical approaches for conditions in which Trp metabolism is dysregulated.
Kynurenine-dependent redox signaling at the interface between innate and adaptive immunity. Supported by an R01 award from the National Institute of Allergy and Infectious Diseases (R01AI178864), this project explores the immunomodulatory actions of a novel pathway in myeloid-lineage cells that yields Kyn‑CKA. This metabolite reacts covalently with cysteine residues in transcriptional regulatory proteins and enzymes to elicit immunomodulatory signaling. We are harnessing cell and mouse models together with bio-orthogonal labeling strategies and isotope-tracing metabolic flux analyses to define the mechanism of the anti-inflammatory actions of Kyn-CKA. The ability of Kyn-CKA to modulate acute inflammation and tolerogenic responses is explored by assessing its effect on the maturation and activation of dendritic cells, its impact on T cell polarization, and its ability to modulate inflammatory responses in vivo. Understanding this pathway could open new therapeutic avenues for limiting auto-immune diseases, transplant rejection and treating chronic inflammation.
Your idea here? Our exploration of tryptophan-derived electrophiles has just begun and there are many questions waiting to be asked! Beyond this pathway, we are very interested in redox biology and particularly in mechanisms of thiol-dependent signaling and in nitric oxide biochemistry.
