IOO1+P2H7 Dual Inhibitors 2017

http://www.sciencedirect.com/science/article/pii/S1074761316300541

Heme dioxygenases are a family of enzymes that include indoleamine 2,3-dioxygenase 1 and 2 (IDO1 and IDO2), as well as tryptophan 2,3-dioxygenase (TDO).

 

These catalyze the initial and rate-limiting step of tryptophan degradation in the kynurenine pathway:

L-tryptophan + O2 -> N-formyl-L-kynuren (Munn and Mellor, 2013).

IDO1 expression is induced by various agonists in macrophages while TDO is expressed mainly in parenchyma cells (Munn and Mellor, 2013).

 

The product of heme dioxygenases, i.e., N-formyl-L-kynuren, is sensed in macrophages via the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that modulates macrophage activation (Bessede et al., 2014; Stockinger et al., 2014).

 

 

Heme-iron metabolism can regulate this signal transduction pathway at different levels: (i) restricting heme availability for expression and activity of heme dioxygenases; (ii) Modulating enzymatic activity via CO binding to ferrous heme (Brady, 1975), or (iii) via the production of biliverdin, an end product of heme catabolism by HO-1 sensed by AhR (Phelan et al., 1998).

 

 

 

Given the central role played by AhR in the regulation of both macrophage and T cell activation, modulation of this pathway by heme-iron catabolism is likely to impact macrophage and/or T cell activation. This remains however to be tested experimentally.