The kynurenine pathway in chronic diseases: a compensatory mechanism or a driving force?. Issue 10 (October 2021)

• Record Type: Journal Article
• Authors: Joisten, Niklas; Ruas, Jorge L.; Braidy, Nady; Guillemin, Gilles J.; Zimmer, Philipp
• Is Part Of: Trends in molecular medicine. Volume 27:Issue 10(2021)
• Page Start: 946
• Page End: 954
• Publication Date: 2021-10
• Subjects: tryptophan -- metabolism -- kynurenines -- inflammation -- bioenergetics; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; Physiology, Pathological -- Periodicals; 572.8
• DOI: 10.1016/j.molmed.2021.07.006
• Languages: English
• ISSNs: 1471-4914

Abstract

Abstract : The kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism is dysregulated in inflammation-driven pathologies including oncological and brain diseases [e.g., multiple sclerosis (MS), depression] and thus is a promising therapeutic target. Both pathological and compensatory mechanisms underlie disease-associated KP activation. There is growing evidence for bioenergetic roles of certain KP metabolites such as kynurenic acid (KA), or quinolinic acid (QA) as an NAD + precursor, which may explain its frequently observed 'pathological' overactivation. Disease- and tissue-specific aspects, negative feedback on inflammatory signals, and the balance of downstream metabolites are likely to be decisive factors in the interpretation of an imbalanced KP. Therapeutic strategies should consider the compensatory actions and bioenergetic roles of KP metabolites to successfully design future theragnostic approaches aimed at attenuating disease progression. Highlights: The kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation is consistently imbalanced in chronic inflammatory diseases but mediates partly pathological and partly compensatory mechanisms in disease progression. Therapeutic drugs designed to modulate key KP enzymes, such as indoleamine 2, 3-dioxygenase-1 (IDO-1) or KYN aminotransferases (KATs), have entered clinical trials in patients with various oncological diseases and schizophrenia. Interleukin-4-induced-1 is an enzyme recently discovered to regulate the generation of TRP-derived endogenous aryl hydrocarbon receptor (AhR) ligands and represents a potential new therapeutic target, especially in oncological and neurodegenerative diseases. Increased KP metabolism may represent a mechanism to regenerate levels of the pyridine nucleotide NAD +, which is essential to the continued viability of cells.