title: Human indoleamine 2,3-dioxygenase-2 has substrate specificity and inhibition characteristics distinct from those of indoleamine 2,3-dioxygenase-1.
abstract: Indoleamine 2,3-dioxygenase-2 (IDO2) is one of three enzymes (alongside tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase (IDO1)) that catalyse dioxygenation of L-tryptophan as the first step in the kynurenine pathway. Despite the reported expression of IDO2 in tumours, some fundamental characteristics of the enzyme, such as substrate specificity and inhibition selectivity, are still to be clearly defined. In this study, we report the kinetic and inhibition characteristics of recombinant human IDO2. Choosing from a series of likely IDO2 substrates, we screened 54 tryptophan derivatives and tryptophan-like molecules, and characterised the 8 with which the enzyme was most active. Specificity of IDO2 for the two isomers of 1-methyltryptophan was also evaluated and the findings compared with those obtained in other studies on IDO2 and IDO1. Interestingly, IDO2 demonstrates behaviour distinct from that of IDO1 in terms of substrate specificity and affinity, such that we have identified tryptophan derivatives that are mutually exclusive as substrates for IDO1 and IDO2. Our results support the idea that the antitumour activity of 1-Me-D-Trp is unlikely to be related with competitive inhibition of IDO2, and also imply that there are subtle differences in active site structure in the two enzymes that may be exploited in the development of specific inhibitors of these enzymes, a route which may prove important in defining their role(s) in cancer.
authors.affiliation: EaStCHEM, School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, UK.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pantouris
authors.forename: Martynas
authors.initials: M
authors.lastname: Serys
authors.forename: Hajime J
authors.initials: HJ
authors.lastname: Yuasa
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mowat
mesh_terms: D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013379:Substrate Specificity / Q000502:physiology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C576710:IDO1 protein, human; C576711:IDO2 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011994:Recombinant Proteins; C028129:tryptophan methyl ester; D014364:Tryptophan