Metabolism of the essential amino acid tryptophan is mediated largely by indoleamine 2,3-dioxygenase (IDO1), a heme protein that accounts for ~ 95% of Trp catabolism. The first intermediate in this signaling pathway is <i>N-</i>formylkynurenine, which is subsequently transformed into kynurenine and eventually niacin and NAD. IDO1 is highly upregulated in response to the aryl hydrocarbon receptor and cytokine-induced inflammation. Significantly, many types of cancer cells over-express IDO1 to deplete tryptophan, which inactivates surrounding immune cells through the combined effects of low tryptophan and higher concentrations of kynurenine. T-cells are especially sensitive to low tryptophan concentrations, causing them to cease proliferation and to differentiate into immunosuppressive regulatory states. Inhibitors of human IDO1 have been widely explored as a means to decrease the ability of cancer cells to avoid immune detection. This kynurenine pathway also effects a wide variety of other processes including autoimmune disorders, response to infection, tolerance in transplantation, HIV infection and blood pressure regulation. In this lecture, we will discuss recent results aimed at elucidating modes of IDO activation and inhibition. In particular, we will discuss IDO1 reaction pathways and reactive intermediates, redox inactivation, heme loss and the surprising activation of IDO1 by physiological levels of polysulfides.

Unraveling the mechanism, immune regulation and inhibition of indoleamine 2,3-dioxygenase

ACS Spring 2022

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