The rate of flux down the tryptophan-kynurenine pathway is determined first by the level of free circulating tryptophan and then by the activity of the enzymes tryptophan 2,3-dioxygenase
(TDO2; heme) in the liver and indoleamine 2,3-dioxygenase 1 and 2 (IDO1, IDO2; heme) elsewhere in the body (Figure 1).
While IFN-[alpha]-stimulated BMM upregulated tryptophan 2,3-dioxygenase
(TDO2) and KMO, stimulation of MDM was associated with the upregulation of KMO and kynureninase (KYNU).
Via the Kyn pathway, the degradation of the other 95% of Trp is converted to kynurenine, and the regulation of this primarily occurs with a pair of rate-limiting enzymes, tryptophan 2,3-dioxygenase
(TDO) and indoleamine 2,3-dioxygenase (IDO1).
Abstract: Tryptophan 2,3-dioxygenase
(TDO) exist only in liver while indoleamine 2, 3-dioxygenase (IDO) exists ubiquitously in the body, these are the most rate-limiting enzymes of kynurenine pathway (KP).
According to the contract, iTeos will license to Pfizer rights to iTeos' pre-clinical compounds targeting Indoleamine 2,3-dioxygenase (IDO1) and Tryptophan 2,3-dioxygenase
(TDO2), while Pfizer will be responsible for the development and commercialisation of IDO1 and TDO2 drug candidates.
The first and rate limiting step of the tryptophan catabolism in mammals is regulated by the enzymes tryptophan 2,3-dioxygenase
(TDO) and indoleamine 2,3-dioxygenase (IDO), which catalyze the conversion of tryptophan to N-formyl kynurenine.
Cirrhotic liver disease patients present with reduced activity of tryptophan 2,3-dioxygenase
(22%), with subsequent increased free tryptophan and half-life, and decreased clearance.
In the kynurenine pathway, tryptophan can be catabolized either by indoleamine 2,3-dioxygenase, which is activated by type 1 cytokines, or by tryptophan 2,3-dioxygenase
is located primarily in the liver, and its activity is up-regulated in response to Trp and metabolic steroids.
reported an impairment in the immunomodulatory and antimicrobial actions of the hepatic enzyme tryptophan 2,3-dioxygenase
, which converts tryptophan, the essential amino acid for hosts and pathogens, to N-formylkynurenine, the precursor of the immune-relevant kynurenines, upon hypoxic conditions mimicking those occurring in vivo during infection and cancer, for example.
The first step of the KP involves the oxidative opening of the tryptophan indole ring by tryptophan 2,3-dioxygenase
(TDO; in the liver) or by indoleamine 2,3-dioxygenase-I and -II (IDO-1 and IDO-2, resp., in the brain) to produce the instable metabolite, N-formylkynurenine [3-5].