Molecular Insights Into the Interaction of Tryptophan Metabolites With Tryptophan and Indoleamine 2,3-Dioxygenases: Nitric Oxide a New Effector of Tryptophan 2,3-Dioxygenase and Their Roles in Infection.

Abstract

Feedback and other negative controls are important determinants of metabolic pathway activities. Other than inhibition of indoleamine 2,3-dioxygenase (IDO) by tryptophan (Trp) and nitric oxide (NO) and feedback inhibition of Trp 2,3-dioxygenase (TDO) by NAD(P)H, little is known of potential effects of Trp and kynurenine metabolites on the kynurenine (Kyn) pathway (KP). Whereas previous studies suggested that some Trp metabolites inhibit TDO activity in vitro, when administered in vivo to rats, inhibition is not always demonstrable, suggesting involvement of mitigating factors. To resolve this difference and provide indicators of likely interaction of Trp metabolites with TDO and IDO1, we performed molecular docking in silico of Trp and a range of its metabolites to these 2 KP enzymes. We found that Trp and many of its Kyn and 5-hydroxyindole metabolites docked to the active site of the TDO2 crystal structure, whereas no docking was observed with Kyn or kynurenic acid. Docking of NAD⁺(P⁺)H occurred at a different site, provisionally identified as the TDO allosteric site. By contrast, docking to IDO1 was limited to Trp, N'-formylkynurenine, 3-hydroxyanthranilic acid and picolinic acid. We conclude that bioinformatics can resolve controversial issues and identify amino acid residues at unexplored sites. The IDO1 effector nitric oxide (NO) docked to TDO as well as to IDO1. NO controls TDO2 and IDO1 activities in a dual fashion, through provision and limitation of the heme cofactor. We propose NO as a new TDO effector and discuss its role in control of TDO during acute inflammation. We propose TDO as an important player in the acute inflammatory responses in parallel with IDO1.