Probing a Novel Substrate Inhibition Mechanism of IDO1

Abstract

Indoleamine dioxygenase 1 aides the complex and exquisite effort of regulating the human immune response. Its role in cancer immune escape has sparked intense research in academia and pharmacology over the past two decades. However, the recent failure of IDO1 target molecules in clinical trials demonstrates an incomplete understanding of its regulation and broader metabolic effects. By probing a novel substrate inhibition mechanism formulated by Nelp et al., this work contributes to a better understanding of IDO1’s inherent regulation. In conclusion, this novel mechanism 1) is not linked to peroxynitrite inactivation, 2) can explain IDO1’s enantiospecific substrate inhibition, 3) can explain dopamine’s ability to lift inhibition, and 4) is complicated by indole ethanol–induced activation.