Small-molecule inhibitors of indoleamine 2,3-dioxygenase (IDO) are currently being translated to clinic for evaluation as cancer therapeutics. One issue related to trials of the clinical lead inhibitor, D-1-methyl-tryptophan (D-1MT), concerns the extent of its biochemical specificity for IDO. Here, we report the discovery of a novel IDO-related tryptophan catabolic enzyme termed IDO2 that is preferentially inhibited by D-1MT. IDO2 is not as widely expressed as IDO but like its relative is also expressed in antigen-presenting dendritic cells where tryptophan catabolism drives immune tolerance. We identified two common genetic polymorphisms in the human gene encoding IDO2 that ablate its enzymatic activity. Like IDO, IDO2 catabolizes tryptophan, triggers phosphorylation of the translation initiation factor eIF2alpha, and (reported here for the first time) mobilizes translation of LIP, an inhibitory isoform of the immune regulatory transcription factor NF-IL6. Tryptophan restoration switches off this signaling pathway when activated by IDO, but not IDO2, arguing that IDO2 has a distinct signaling role. Our findings have implications for understanding the evolution of tumoral immune tolerance and for interpreting preclinical and clinical responses to D-1MT or other IDO inhibitors being developed to treat cancer, chronic infection, and other diseases.
The antiproliferative action of human interferon (HuIFN)-gamma on human cells and the inhibition of intracellular pathogens, e.g. Toxoplasma gondii and Chlamydia psittaci, is at least in part due to an induction of indoleamine 2,3-dioxygenase (IDO) enzyme which degrades tryptophan, an essential amino acid. A cDNA clone (called C42) was isolated from a cDNA library made from poly(A)+ RNA obtained from HuIFN-gamma-treated human fibroblasts. Its nucleotide sequence revealed an open reading frame coding for a polypeptide of 403 amino acids, but no homology with any known gene in GenBank database was found. Evidence was obtained indicating that this cDNA codes for IDO: (i) Hybrid selected C42 specific poly(A)+ RNA from IFN-gamma-treated human cells coded for a polypeptide in vitro of approximately 42 kD (reported size of IDO, approximately 40 kD) which was immunoprecipitated by monoclonal anti-IDO antibody but not by a control antibody; and (ii) transfection of human fibroblasts with an expression plasmid containing C42 cDNA transcribed from chicken beta-actin promoter led to constitutive expression of C42 specific RNA as well as IDO activity. This cDNA clone will be useful in studying the role of IDO in the biological effects of IFN-gamma, and the regulation of IDO gene by IFN-gamma.
Catalysis of the reaction: tryptophan + O2 = N-formylkynurenine. The product of the reaction depends on the substrate; D-tryptophan produces N-formyl-D-kynurenine, and L-tryptophan produces N-formyl-L-kynurenine.
The specific actions or reactions of an organism in response to external or internal stimuli. Patterned activity of a whole organism in a manner dependent upon some combination of that organism's internal state and external conditions.
The synthesis or release of a cytokine following a inflammatory stimulus as part of an inflammatory response, resulting in an increase in its intracellular or extracellular levels.
The set of physiological processes that allow an embryo or foetus to develop within the body of a female animal. It covers the time from fertilization of a female ovum by a male spermatozoon until birth.
In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme expressed by trophoblasts and macrophages. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection.
Any process that results in a change in state or activity of a multicellular organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating the organism is under stress. The stress is usually, but not necessarily, exogenous (e.g. temperature, humidity, ionizing radiation).
Any process that results in a change in state or activity of an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a lipopolysaccharide stimulus; lipopolysaccharide is a major component of the cell wall of gram-negative bacteria.
Small-molecule inhibitors of indoleamine 2,3-dioxygenase (IDO) are currently being translated to clinic for evaluation as cancer therapeutics. One issue related to trials of the clinical lead inhibitor, D-1-methyl-tryptophan (D-1MT), concerns the extent of its biochemical specificity for IDO. Here, we report the discovery of a novel IDO-related tryptophan catabolic enzyme termed IDO2 that is preferentially inhibited by D-1MT. IDO2 is not as widely expressed as IDO but like its relative is also expressed in antigen-presenting dendritic cells where tryptophan catabolism drives immune tolerance. We identified two common genetic polymorphisms in the human gene encoding IDO2 that ablate its enzymatic activity. Like IDO, IDO2 catabolizes tryptophan, triggers phosphorylation of the translation initiation factor eIF2alpha, and (reported here for the first time) mobilizes translation of LIP, an inhibitory isoform of the immune regulatory transcription factor NF-IL6. Tryptophan restoration switches off this signaling pathway when activated by IDO, but not IDO2, arguing that IDO2 has a distinct signaling role. Our findings have implications for understanding the evolution of tumoral immune tolerance and for interpreting preclinical and clinical responses to D-1MT or other IDO inhibitors being developed to treat cancer, chronic infection, and other diseases.
Small-molecule inhibitors of indoleamine 2,3-dioxygenase (IDO) are currently being translated to clinic for evaluation as cancer therapeutics. One issue related to trials of the clinical lead inhibitor, D-1-methyl-tryptophan (D-1MT), concerns the extent of its biochemical specificity for IDO. Here, we report the discovery of a novel IDO-related tryptophan catabolic enzyme termed IDO2 that is preferentially inhibited by D-1MT. IDO2 is not as widely expressed as IDO but like its relative is also expressed in antigen-presenting dendritic cells where tryptophan catabolism drives immune tolerance. We identified two common genetic polymorphisms in the human gene encoding IDO2 that ablate its enzymatic activity. Like IDO, IDO2 catabolizes tryptophan, triggers phosphorylation of the translation initiation factor eIF2alpha, and (reported here for the first time) mobilizes translation of LIP, an inhibitory isoform of the immune regulatory transcription factor NF-IL6. Tryptophan restoration switches off this signaling pathway when activated by IDO, but not IDO2, arguing that IDO2 has a distinct signaling role. Our findings have implications for understanding the evolution of tumoral immune tolerance and for interpreting preclinical and clinical responses to D-1MT or other IDO inhibitors being developed to treat cancer, chronic infection, and other diseases.
Activity is inhibited by and MTH-trp (methylthiohydantoin-DL-tryptophan), modestly inhibited by L-1MT (1-methyl-L-tryptophan) but not D-1MT (1-methyl-D-tryptophan).
Small-molecule inhibitors of indoleamine 2,3-dioxygenase (IDO) are currently being translated to clinic for evaluation as cancer therapeutics. One issue related to trials of the clinical lead inhibitor, D-1-methyl-tryptophan (D-1MT), concerns the extent of its biochemical specificity for IDO. Here, we report the discovery of a novel IDO-related tryptophan catabolic enzyme termed IDO2 that is preferentially inhibited by D-1MT. IDO2 is not as widely expressed as IDO but like its relative is also expressed in antigen-presenting dendritic cells where tryptophan catabolism drives immune tolerance. We identified two common genetic polymorphisms in the human gene encoding IDO2 that ablate its enzymatic activity. Like IDO, IDO2 catabolizes tryptophan, triggers phosphorylation of the translation initiation factor eIF2alpha, and (reported here for the first time) mobilizes translation of LIP, an inhibitory isoform of the immune regulatory transcription factor NF-IL6. Tryptophan restoration switches off this signaling pathway when activated by IDO, but not IDO2, arguing that IDO2 has a distinct signaling role. Our findings have implications for understanding the evolution of tumoral immune tolerance and for interpreting preclinical and clinical responses to D-1MT or other IDO inhibitors being developed to treat cancer, chronic infection, and other diseases.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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