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bioRxiv · 10.1101/2024.11.15.623703

N-formylkynurenine but not kynurenine enters a nucleophile-scavenging branch of the immune-regulatory kynurenine pathway

Wang, Y.·Leung, E. Y.·Tomek, P.
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Abstract

Tryptophan catabolism along the kynurenine pathway (KP) mediates key physiological functions ranging from immune tolerance to lens UV protection, but the contributory roles and chemical fates of individual KP metabolites are incompletely understood. This particularly concerns the first KP metabolite, N-formylkynurenine (NFK), canonically viewed as a transient precursor to the downstream kynurenine (KYN). Here, we challenge that canon and show that hydrolytic enzymes act as a rheostat switching the fate of NFK between the canonical KP and a novel non-enzymatic branch of tryptophan catabolism. In the physiological environment (37{degrees}C, pH 7.4), NFK deaminated into electrophilic NFK- carboxyketoalkene (NFK-CKA), which rapidly (< 2 minutes) formed adducts with nucleophiles such as cysteine and glutathione, the key intracellular antioxidants. Serum hydrolases suppressed NFK deamination as they hydrolysed NFK to KYN [~]3 times faster than NFK deaminates. Whilst KYN did not deaminate, its deaminated product (KYN-CKA) rapidly reacted with cysteine but not glutathione. The new NFK transformations of yet to be confirmed functions highlight significance of NFK beyond hydrolysis to KYN and suggests the dominance of its chemical transformations over those of KYN in physiological environments. Enzyme compartmentalisation and abundance offer insights into the regulation of non-enzymatic NFK and KYN transformations that are emerging as contributors to immune regulation, protein modification, lens aging or neuropathology.

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Wang, Y., Leung, E. Y., Tomek, P.. 2024-11-16. N-formylkynurenine but not kynurenine enters a nucleophile-scavenging branch of the immune-regulatory kynurenine pathway. https://doi.org/10.1101/2024.11.15.623703

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