INDOLEAMINE 2,3 DIOXYGENASE-1: THE BIPHASIC NATURE OF ITS FERRYL TO FERRIC REDUCTION AND THE SIGNIFICANCE OF TRYPTOPHAN ELECTRON DENSITY IN BINDING TO ITS FERRYLO FORM

Abstract

Indoleamine 2,3 dioxygenase (IDO1) is a heme protein that facilitates the rate determining step of tryptophan (Trp) metabolism into kynurenine (Kyn). Years after its discovery, it was discovered that this same heme protein is acts as an immunosuppressant as decreasing Trp and increasing Kyn results in a dampened immune response. In this paper, the formation of IDO1’s ferryl species through the use of peroxynitrite and subsequent return to its ferric form is examined in two ways. First, the return to ferric in the presence of variable Trp concentrations in order to show that a double exponential fit is more prudent than a single exponential fit, providing a new KD. Second, variants of Trp are used to provide evidence that increased electron density of Trp increases the rate of the ferryl species’ return to ferric. This suggests that the aromatic ring of Trp may itself be assisting in transferring electrons to the heme protein in order to reduce it.