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Heme-containing Enzymes and Inhibitors for Tryptophan Metabolism


Iron-containing enzymes such as heme enzymes play crucial roles in biological systems. Three distinct heme-containing dioxygenase enzymes, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the initial and rate-limiting step of L-tryptophan catabolism through the kynurenine pathway in mammals. Overexpression of these enzymes causes depletion of tryptophan and accumulation of metabolic products, which contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies. In the past decades, IDO1 has garnered the most attention as one of the most potential therapeutic targets in cancer immunotherapy. Many potential inhibitors of IDO1 have been designed, synthesized and evaluated, among which indoximod (D-1-MT), INCB024360, GDC-0919 (formerly NLG-919), and an IDO1 peptide-based vaccine have advanced to clinical trial stage. However, until recently, the roles of TDO and IDO2 have been elucidated in immune suppression. In this review, the current drug discovery landscape for targeting TDO, IDO1 and IDO2 are highlighted, with particular attention to the recent use of drugs in clinical trial. Moreover, the crystal structures of these enzymes, in complex with inhibitors, and the mechanisms of Trp catabolism in first step, are summarized here to provide information for facilitating the discovery of new enzyme inhibitors.

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Publication details

The article was received on 06 Apr 2017, accepted on 07 Jun 2017 and first published on 07 Jun 2017

Article type: Critical Review
DOI: 10.1039/C7MT00105C
Citation: Metallomics, 2017, Accepted Manuscript
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    Heme-containing Enzymes and Inhibitors for Tryptophan Metabolism

    X. Tan, D. Yan and Y. Lin, Metallomics, 2017, Accepted Manuscript , DOI: 10.1039/C7MT00105C

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