New insights into the molecular properties of human indoleamine 2,3-dioxygenase 2

Human indoleamine 2,3-dioxygenases 1 and 2 (IDO1 and IDO2) and tryptophan dioxygenase (TDO) catalyze the dioxygenation of L-tryptophan (L-Trp) to N-formylkynurenine, the first and rate-limiting step of the kynurenine pathway. All three enzymes have recently emerged as important targets for cancer immunotherapy. While the molecular and structural properties of IDO1 and TDO have been extensively investigated over the past several decades, comparatively little is known about the more recently discovered IDO2, hindering the development of enzyme-selective inhibitors. Unlike IDO1 and TDO, which efficiently catalyze the Trp dioxygenation reaction, IDO2 exhibits markedly low activity, with a K M value in the millimolar range, far exceeding the physiological concentration of L-Trp. This unusual property raises important questions regarding the physiological role and functional mechanism of IDO2. In this work, we employed resonance Raman and Fourier transform infrared spectroscopy to investigate the molecular properties of IDO2. Comparison with IDO1 revealed that IDO2 possesses a substantially more flexible active-site architecture, weaker ligand-substrate interactions, and more dynamic substrate-protein interactions. These distinctive structural features likely contribute to the unusually low dioxygenase activity of IDO2.