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Formation, metabolism and cell signaling actions of tryptophan catabolism-derived electrophiles

Award Number: R35GM152083
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Formation, metabolism and cell signaling actions of tryptophan catabolism-derived electrophiles - Under steady-state conditions, >90% of tryptophan (Trp) catabolism occurs in the liver via the kynurenine (Kyn) pathway. However, this process has important pathophysiological roles in the brain, kidneys and heart, as well as in modulating immunity, tumor microenvironments, and pregnancy. Altered Kyn metabolism is observed in aging, cardiovascular disease, organ injury, cancer, and transplantation, where it often is a strong predictor of outcome. Despite their relevance, the mechanisms behind the effects resulting from changes in systemic and local Kyn metabolism are poorly defined. Using untargeted and targeted mass spectrometry together with isotopically labeled standards, we discovered the endogenous formation of the electrophilic mediator kynurenine- carboxyketoalkene (Kyn-CKA) secondary to in vivo Kyn deamination in humans and mice. Kyn-CKA reacts covalently with cysteine residues in transcription factors, transcriptional regulatory proteins and enzymes to regulate protein and cellular function. We recently published that Kyn-CKA modulates TLR/NF-κB- and Keap1/Nrf2-dependent signaling and our preliminary data shows that Kyn-CKA also affects bioenergetic metabolism and impacts seemingly cysteine-independent processes. Furthermore, we now know that N-formyl- kynurenine (NFK) and 3-hydroxy-kynurenine (OH-Kyn) also generate electrophiles in vivo. We hypothesize that Trp catabolism via the Kyn pathway results in the formation of novel bioactive products that adaptively modulate cellular responses via redox-dependent mechanisms. We propose to characterize the mechanisms that regulate the formation of Trp-derived electrophiles via modulation of individual enzymes in the Kyn pathway and the identification of potential enzymes capable of catalyzing NFK, Kyn and OH-Kyn deamination. Trp-derived electrophiles undergo conjugation to glutathione and reductive inactivation, thus we will identify and kinetically characterize the enzymes involved in these processes. Unbiased high resolution mass spectrometry and isotopically labeled precursors will be used to discover pathways for inactivation and biotransformation of Trp- derived electrophiles. Furthermore, we will characterize the effects of Trp-derived electrophiles on cellular and tissue bioenergetic metabolism, first using hepatocytes and then expanding to other cell types as informed by in vivo formation data. In this regard, we will establish the impact of dietary Trp intake regulation on systemic and tissue Trp-derived electrophile levels, as well as assess a potential contribution of the microbiome to this process. Finally, we will use spatial transcriptomics in conjunction with click chemistry-dependent labeling strategies to elucidate the sites of azido-Kyn deamination in vivo and define the impact of this process on electrophile-targeted and untargeted regions of interest to differentiate between proximal and paracrine signaling effects. Overall, our discovery that the Kyn pathway is a source of bioactive electrophiles has the potential to transform our understanding of Trp biology. We expect our research provide a solid biochemical foundation that will enable the development of novel clinical approaches for conditions in which Trp metabolism is dysregulated.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $371,250 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	3	5/28/2026	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2025 ( Subtotal = $371,250 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	001	2	5/26/2025	NON-COMPETING CONTINUATION	$371,250
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	1	11/5/2024	NEW	$0
														Subtotal = $371,250

Issue Date FY: 2024 ( Subtotal = $371,250 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Biomedical Research and Research Training	000	1	6/28/2024	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,113,750

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Formation, metabolism and cell signaling actions of tryptophan catabolism-derived electrophiles

Award Number: R35GM152083

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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