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IDO

IDO is a key enzyme in the catabolism of tryptophan to kynurenine. IDO activity causes a decrease in tryptophan levels and thus an accumulation of uncharged tryptophan transfer RNA (Trp-tRNA). Higher levels of Trp-tRNA result in the activation of general control non-derepressible 2 (GCN2), a stress-response kinase, which phosphorylates eukaryotic initiation factor-2 (eIF-2). eIF-2 phosphorylation limits protein translation, ultimately leading to decreased T-efector cell proliferation. Mammalian target of rapamycin complex 1 (mTORC1) is suppressed in settings of tryptophan depletion. Tryptophan degradation results in blockade of master amino acid-sensing kinase glucokinase 1 (GLK1) and suppression of mTORC1. Activated mTORC1 inhibits autophagy. Relief of this inhibition allows autophagy to proceed, leading to increased T-efector cell apoptosis. Finally, by catabolizing tryptophan, IDO leads to an increase in kynurenine, which binds to the aryl hydrocarbon receptor, causing the diferentiation of T-regulatory cells (Tregs) that suppress antitumor immune responses. IDO also exerts immunosuppressive efects by augmenting interleukin (IL)-6, a known driver of immunosuppressive myeloidderived suppressor cells (MDSCs). Finally, IDO is selfrenewing, as increased kynurenine levels can lead to further IDO expression by dendritic cells.

References

1.Yentz S,et al. BioDrugs. 2018 Aug;32(4):311-317.

Metabolic Enzyme/Protease

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