Indoleamine 2, 3- Dioxygenases 2: The Missing Link For The 1-methyl-D-trp Mechanism Of Action?

Abstract

Indoleamine 2, 3-dioxygenase (IDO1) is one of the only two heme-containing enzymes that catalyze the first and rate-limiting step of the kynurenine pathway of L-Trp metabolism. IDO1 has been implicated in the escape mechanism of cancer cells from immune surveillance. Consequently, IDO1 has been recognized as an important anticancer drug target. Recent studies showed that an IDO1 inhibitor, 1-methyl-Trp (1-M-Trp), triggers antitumor immunity and can be used to improve the efficacy of traditional chemotherapeutic drugs. Preclinical studies showed that the D stereoisomer of 1-M-Trp exhibits superior antitumor activity; however, it is less potent for the purified enzyme. On this basis, a second isoform of IDO1 had been suspected. It was not until last year that this second isoform of IDO1, named IDO2, was identified. To understand the missing link for the D-1-M-Trp mechanism of action, we have cloned, expressed and purified recombinant human IDO2. Resonance Raman and optical absorption spectroscopic studies showed that IDO2 exhibits structural features slightly different from IDO1. Furthermore, an activity assay with D- or L-Trp shows that IDO2 does not produce N'-Formyl-kynurenine as IDO1 does; instead, a new product with an absorption maximum at 344 nm was produced. Stopped-flow measurements show that IDO2 binds O2 in a similar fashion as IDO1. Together these data indicate novel function and action mechanisms of IDO2 that are distinctive from IDO1.