680C91, tryptophan 2,3-dioxygenase inhibitor

Supplementary information

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TDO2 also known as tryptophan 23-dioxygenase is an enzyme that catalyzes the initial and rate-limiting step in the kynurenine pathway degrading tryptophan to N-formylkynurenine. This reaction is important for regulating systemic tryptophan levels. TDO2 is a heme-containing enzyme with a molecular mass of approximately 53 kDa. It is highly expressed in the liver unlike its counterpart indoleamine 23-dioxygenase (IDO) which has wider tissue distribution. Liver-specific expression suggests its role in orchestrating whole-body tryptophan metabolism.

Biological function summary

TDO2 plays a significant role in maintaining immune tolerance and modulating neurotransmitter levels. While not part of a larger complex it interacts with several other proteins to mediate its effects. By controlling tryptophan availability TDO2 impacts the production of serotonin and downstream kynurenine metabolites affecting neural and immune functions. Its activity influences both central nervous system processes and peripheral immune responses implying a broad impact on various physiological systems.

Pathways

TDO2's function integrates into the kynurenine and serotonin pathways. In the kynurenine pathway TDO2's enzymatic activity leads to the generation of metabolites such as kynurenine and quinolinic acid which have immunoregulatory and excitotoxic properties. The serotonin pathway also indirectly involves TDO2 as it limits tryptophan's availability for serotonin synthesis. TDO2 interacts with IDO in controlling the balance of tryptophan metabolites providing a link between immune signaling and central nervous system regulation.

TDO2 has been implicated in cancer and neurodegenerative diseases. Overexpression of TDO2 is observed in various cancers where it helps create an immune-suppressive environment that aids tumor survival. The enzyme’s upregulation affects tumor microenvironment dynamics often acting in concert with IDO which further mediates immune escape. TDO2's activity may also contribute to neurodegenerative disorders through its impact on kynurenine pathway metabolites which can be neurotoxic. The interplay between TDO2 and IDO suggests that targeting this enzymatic pathway could offer therapeutic avenues in both oncological and neuropsychiatric conditions.