Indoleamine 2,3-dioxygenase 1

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The IDO1 gene at 8p11.21 codes for the 403 amino acid pro-peptide to the key enzyme indoleamine 2,3-dioxygenase 1 that allows cancer cells to escape immunoregulation. This catalyzes the initial rate limiting step of the breakdown of the essential amino acid tryptophan along the kynurenine pathway. This pathway can be used to produce neuroactive metabolites, such as kynurenine, kynurenic acid, 3-hydroxykynurenine, and quinolinic acid which can be responsible for neuroexcitotoxicity. As tryptophan shortage inhibits T-cell division and accumulation of tryptophan metabolites induces apoptosis and differentiation of T-cells this is quite important, especially in dealing with neoplastic cells[1]. [Indoleamine 2,3-dioxygenase 1]] is involved in peripheral immune tolerance homeostasis and is usually only expressed in cells of the immune system. It acts as a suppressor of anti-tumour immunity and limits the growth of intracellular pathogens such as malaria by depriving them of tryptophan. It is over expressed in inflammatory bowel disease but probably because it acts as a natural break to ongoing inflammation. It has a role in protecting the fetus from maternal immune rejection[2]. Another gene IDO2 codes for the alternative enzyme indoleamine 2,3-dioxygenase 2 which is much more rarely expressed to excess in malignant cells, but widely expressed in most non immune tissues. At least one variant of IDO2 is protective against Crohns disease[3]. Both are active with a heme group in its ferrous state and catalyse the reaction:

L-tryptophan+ O2 => N-formyl-L-kynurenine

Oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors are in clinical development as a form of immuno-oncological therapy[4]. These include epacadostat[5] (INCB024360) and SN38437.