Kynurenine Pathway Regulation at Its Critical Junctions with Fluctuation of Tryptophan

dc.contributor.authorNewton, Ashley
dc.contributor.authorMcCann, Luree
dc.contributor.authorHuo, Lu
dc.contributor.authorLiu, Aimin
dc.description.abstractThe kynurenine pathway (KP) is the primary route for the catabolism of the essential amino acid tryptophan. The central KP metabolites are neurologically active molecules or biosynthetic precursors to critical molecules, such as NAD+. Within this pathway are three enzymes of interest, HAO, ACMSD, and AMSDH, whose substrates and/or products can spontaneously cyclize to form side products such as quinolinic acid (QA or QUIN) and picolinic acid. Due to their unstable nature for spontaneous autocyclization, it might be expected that the levels of these side products would be dependent on tryptophan intake; however, this is not the case in healthy individuals. On top of that, the regulatory mechanisms of the KP remain unknown, even after a deeper understanding of the structure and mechanism of the enzymes that handle these unstable KP metabolic intermediates. Thus, the question arises, how do these enzymes compete with the autocyclization of their substrates, especially amidst increased tryptophan levels? Here, we propose the formation of a transient enzyme complex as a regulatory mechanism for metabolite distribution between enzymatic and non-enzymatic routes during periods of increased metabolic intake. Amid high levels of tryptophan, HAO, ACMSD, and AMSDH may bind together, forming a tunnel to shuttle the metabolites through each enzyme, consequently regulating the autocyclization of their products. Though further research is required to establish the formation of transient complexation as a solution to the regulatory mysteries of the KP, our docking model studies support this new hypothesis.
dc.identifierdoi: 10.3390/metabo13040500
dc.identifier.citationMetabolites 13 (4): 500 (2023)
dc.rightsAttribution 4.0 United States
dc.subjecttryptophan metabolism
dc.subjectenzyme complexation
dc.subjectprotein structure
dc.subjectprotein–protein interaction
dc.subjectcatabolic pathway
dc.subjectmetabolic intermediates
dc.titleKynurenine Pathway Regulation at Its Critical Junctions with Fluctuation of Tryptophan


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