Indoleamine 2,3-dioxygenase | |||||||||
---|---|---|---|---|---|---|---|---|---|
![]() crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase | |||||||||
Identifiers | |||||||||
Symbol | IDO | ||||||||
Pfam | PF01231 | ||||||||
Pfam clan | CL0380 | ||||||||
InterPro | IPR000898 | ||||||||
PROSITE | PDOC00684 | ||||||||
|
Indoleamine 2,3-dioxygenase | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
EC no. | 1.13.11.52 | ||||||||
CAS no. | 9014-51-1 | ||||||||
Databases | |||||||||
IntEnz | IntEnz view | ||||||||
BRENDA | BRENDA entry | ||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
|
Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is a heme-containing enzyme physiologically expressed in a number of tissues and cells, such as the small intestine, lungs, female genital tract or placenta. [5] In humans is encoded by the IDO1 gene. [6] IDO is involved in tryptophan metabolism. It is one of three enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O2-dependent oxidation of L-tryptophan to N-formylkynurenine, the others being indolamine-2,3-dioxygenase 2 (IDO2) [7] and tryptophan 2,3-dioxygenase (TDO). [8] IDO is an important part of the immune system and plays a part in natural defense against various pathogens. [9] [10] It is produced by the cells in response to inflammation and has an immunosuppressive function because of its ability to limit T-cell function and engage mechanisms of immune tolerance. [11] Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system. Expression of IDO has been described in a number of types of cancer, such as acute myeloid leukemia, ovarian cancer or colorectal cancer. IDO is part of the malignant transformation process and plays a key role in suppressing the anti-tumor immune response in the body, so inhibiting it could increase the effect of chemotherapy as well as other immunotherapeutic protocols. [12] [13] [14] Furthermore, there is data implicating a role for IDO1 in the modulation of vascular tone in conditions of inflammation via a novel pathway involving singlet oxygen. [15]
Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway.
IDO is an important molecule in the mechanisms of tolerance and its physiological functions include the suppression of potentially dangerous inflammatory processes in the body. [16] IDO also plays a role in natural defense against microorganisms. Expression of IDO is induced by interferon-gamma, which explains why the expression increases during inflammatory diseases or even during tumorigenesis. [17] Since tryptophan is essential for the survival of pathogens, the activity of enzyme IDO destroys them. Microorganisms susceptible to tryptophan deficiency include bacteria of genus Streptococcus [18] or viruses such as herpes simplex [19] or measles. [20]
One of the organs with high IDO expression is the placenta. In the 1990s, the immunosuppressive function of this enzyme was first described in mice due to the study of placental tryptophan metabolism. Thus, mammalian placenta, due to intensive tryptophan catabolism has the ability to suppress T cell activity, thereby contributing to its position of immunologically privileged tissue. [21]
IDO is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by alternatively activated macrophages and other immunoregulatory cells. [22] IDO is known to suppress T and NK cells, generate Tregs and myeloid-derived suppressor cells, and also supports angiogenesis. [12]
These mechanisms are crucial in the process of carcinogenesis. IDO allows tumor cells to escape the immune system by two main mechanisms. The first mechanism is based on tryptophan depletion from the tumor microenvironment. [23] The second mechanism is based on the production of catabolic products called kynurenins, that are cytotoxic for T lymphocytes and NK cells. [24] Overexpression of human IDO (hIDO) is described in a variety of human tumor cell lineages and is often associated with poor prognosis. [25] [26] Tumors with increased production of IDO include prostate, ovarian, lung or pancreatic cancer or acute myeloid leukemia. [27] [28] Expression of IDO is under physiological conditions regulated by the Bin1 gene, which can be damaged by tumor transformation. [29]
Emerging clinical studies suggest that combination of IDO inhibitors with classical chemotherapy and radiotherapy could restore immune control and provide a therapeutic response to generally resistant tumors. Enzyme IDO used by tumors to escape immune surveillance is currently in focus of research and drug discovery efforts, [30] as well as efforts to understand if it could be used as a biomarker for prognosis. [31]
COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.[ citation needed ]
1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase, but is also a very slow substrate. The specific racemer 1-methyl-D-tryptophan (known as indoximod) is in clinical trials for various cancers.
Epacadostat (INCB24360), navoximod (GDC-0919), and linrodostat (BMS-986205) are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers.
Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa (endometrium), prostate, bone marrow, lymph node and the ovary. They are cells that support the function of the parenchymal cells of that organ. The most common stromal cells include fibroblasts and pericytes. The term stromal comes from Latin stromat-, "bed covering", and Ancient Greek στρῶμα, strôma, "bed".
Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.
l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.
The Eutherian Fetoembryonic Defense System(eu-FEDS) is a hypothetical model describing a method by which immune systems are capable of recognizing additional states of relatedness like "own species" such as is observed in maternal immune tolerance in pregnancy. The model includes descriptions of the proposed signaling mechanism and several proposed examples of exploitation of this signaling in disease states.
Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.
Lankenau Institute for Medical Research (LIMR), founded in 1927, is a nonprofit, biomedical research institute located on the campus of Lankenau Medical Center in Wynnewood, Pennsylvania, serving as the research division of the Main Line Health System in suburban Philadelphia. LIMR focuses on studies of cancer, cardiovascular, autoimmune, gastrointestinal and other diseases. It houses a center for population health research.
N′-Formylkynurenine is an intermediate in the catabolism of tryptophan. It is a formylated derivative of kynurenine. The formation of N′-formylkynurenine is catalyzed by heme dioxygenases.
In enzymology, tryptophan 2,3-dioxygenase (EC 1.13.11.11) is a heme enzyme that catalyzes the oxidation of L-tryptophan (L-Trp) to N-formyl-L-kynurenine, as the first and rate-limiting step of the kynurenine pathway.
Programmed death-ligand 1 (PD-L1) also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) is a protein that in humans is encoded by the CD274 gene.
Chronic systemic inflammation (SI) is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune and neurodegenerative disorders, and coronary heart disease.
Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on the oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine triphosphate (ATP) generation to xenobiotic degradation, the use of dioxygen as a biological oxidant is widespread and varied in the exact mechanism of its use. Enzymes employ many different schemes to use dioxygen, and this largely depends on the substrate and reaction at hand.
Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.
Kynurenine 3-monooxygenase is an enzyme that in humans is encoded by the KMO gene.
The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for total catabolization of tryptophan about 95%. Disruption in the pathway is associated with certain genetic and psychiatric disorders.
1-Methyltryptophan is a chemical compound that is an inhibitor of the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase. It is a chiral compound that can exist as both D- and L-enantiomers.
George C. Prendergast is an American biomedical scientist. His research has focused on cancer pathobiology and immunology. Since 2004, he has been the President and CEO of Lankenau Institute for Medical Research, a cancer-focused research center in the U.S. He is also the co-director of the Program in Cancer Cell Biology & Signaling at the Sidney Kimmel Cancer Center, Thomas Jefferson University.
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.
Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.
Indoleamine 2,3-dioxygenase 2 (IDO2) is a protein that in humans is encoded by the IDO2 gene.
Linrodostat is an experimental drug being studied for its immunomodulating and antineoplastic activities.