Interaction of tryptophan metabolites with the human aryl hydrocarbon
receptor in silico: tryptophan as antagonist and failure of kynurenine
to dock
Abstract
It is almost universally thought that modulation of immune function by
tryptophan (Trp) metabolites involves activation of the aryl hydrocarbon
receptor (AhR) mainly by kynurenine (Kyn), based on enhanced expression
of cytochrome P-450 enzymes and their increased activities in cell
systems and in vivo. However, DiNatale et al. (Toxicol. Sci. 2010; 115:
89-97) reported the failure of Kyn at 10 M to activate the AhR, whereas
a similar concentration of kynurenic acid (KA) was effective. The recent
study by Solvay et al (J Immunother Cancer 2023; 11: e006728) called
into question the direct link between Kyn and the AhR and demonstrated
down regulation of the AhR by Trp. In the present study, we have
performed for the first time molecular docking in silico to the human
AhR of the above and a range of other Trp metabolites produced in the
various degradative pathways and by gut microbiota. We demonstrate that,
of 29 Trp metabolites, only Kyn and 3-hydroxykynurenine fail to dock to
the AhR and propose that AhR activation by Kyn is an indirect effect
mediated by KA. The strongest docking is observed with FICZ
(6-Formylindolo[3,2-b]carbazole), cinnabarinic acid,
5-hydroxytryptophan, N-acetyl serotonin and indol-3-yllactic acid. We
propose that Trp, which docks strongly to the AhR is an AhR antagonist.
Differences in AhR activation by Trp metabolites in cell systems and in
vivo may be determined by the prevailing physiological conditions. The
strong docking of 5-hydroxyindoles to the AhR may underpin the effects
of serotonin pathway metabolites on biological processes.