Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO ) is a heme-containing

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

physiologically expressed in a number of tissues and

cells Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a d ...

, such as the

small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

s, female genital tract or

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

. In humans is encoded by the ''IDO1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. IDO is involved in tryptophan

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. It is one of three enzymes that catalyze the first and rate-limiting step in the

kynurenine pathway 400px, The kynurenine pathway 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, xa ...

, the O₂-dependent oxidation of -tryptophan to ''N''-formylkynurenine, the others being indolamine-2,3-dioxygenase 2 (IDO2) and tryptophan 2,3-dioxygenase (TDO). IDO is an important part of the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

and plays a part in natural defense against various

pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...

s. It is produced by the cells in response to

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

and has an

immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...

function because of its ability to limit

T-cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

function and engage mechanisms of

immune tolerance Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specif ...

. 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 Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

, ovarian cancer or

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...

. 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 Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

as well as other immunotherapeutic protocols. Furthermore, there is data implicating a role for IDO1 in the modulation of

vascular tone Vascular resistance is the resistance that must be overcome for blood to flow through the circulatory system. The resistance offered by the systemic circulation is known as the systemic vascular resistance or may sometimes be called by another ter ...

in conditions of inflammation via a novel pathway involving

singlet oxygen Singlet oxygen, systematically named dioxygen(singlet) and dioxidene, is a gaseous inorganic chemistry, inorganic chemical with the formula O=O (also written as or ), which is in a quantum state where all electrons are Radical (chemistry), spin p ...

Physiological function

Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...

through the

kynurenine -Kynurenine is a metabolite of the amino acid -tryptophan used in the production of niacin. Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygena ...

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. IDO also plays a role in natural defense against

microorganism A microorganism, or microbe, is an organism of microscopic scale, microscopic size, which may exist in its unicellular organism, single-celled form or as a Colony (biology)#Microbial colonies, colony of cells. The possible existence of unseen ...

s. Expression of IDO is induced by

interferon-gamma Interferon gamma (IFNG or 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. ...

, which explains why the expression increases during inflammatory diseases or even during

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...

. 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 ''Streptococcus'' is a genus of gram-positive spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occurs along a sing ...

'' or viruses such as

herpes simplex Herpes simplex, often known simply as herpes, is a viral disease, viral infection caused by the herpes simplex virus. Herpes infections are categorized by the area of the body that is infected. The two major types of herpes are Cold sore, ora ...

measles Measles (probably from Middle Dutch or Middle High German ''masel(e)'', meaning "blemish, blood blister") is a highly contagious, Vaccine-preventable diseases, vaccine-preventable infectious disease caused by Measles morbillivirus, measles v ...

. One of the organs with high IDO expression is the

. In the 1990s, the immunosuppressive function of this

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.

Clinical significance

IDO is an

immune checkpoint 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 stimulat ...

molecule in the sense that it is an

immunomodulator Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

y enzyme produced by alternatively activated macrophages and other immunoregulatory cells. IDO is known to suppress T and

NK cell Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells ...

s, generate

Treg The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immun ...

s and myeloid-derived suppressor cells, and also supports

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

. These mechanisms are crucial in the process of

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cell (biology), cells are malignant transformation, transformed into cancer cells. The process is characterized by changes at the cellular, G ...

. IDO allows tumor cells to escape the

by two main mechanisms. The first mechanism is based on tryptophan depletion from the

tumor microenvironment The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue (including blood vessels, immune cells, fibroblasts and signaling molecules) and the extracellular matrix. Mutual interaction between ...

. The second mechanism is based on the production of catabolic products called kynurenins, that are cytotoxic for

T lymphocytes T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes A lymphocyte is a type of white blood cell (leukoc ...

and

NK cells Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cell ...

. Overexpression of human IDO (hIDO) is described in a variety of human tumor cell lineages and is often associated with poor

prognosis Prognosis ( Greek: πρόγνωσις "fore-knowing, foreseeing"; : prognoses) is a medical term for predicting the likelihood or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) ...

. Tumors with increased production of IDO include

prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...

ovarian The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endoc ...

pancreatic The pancreas (plural pancreases, or pancreata) is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

cancer or

. Expression of IDO is under physiological conditions regulated by the ''Bin1'' gene, which can be damaged by tumor transformation. Emerging clinical studies suggest that combination of IDO inhibitors with classical

and

radiotherapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a treatment using ionizing radiation, generally provided as part of cancer therapy to either kill or control the growth of malignant cells. It is normally delivered by a linear particle ...

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 In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or ...

efforts, as well as efforts to understand if it could be used as a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

for prognosis.

Inhibitors

COX-2 inhibitors Cyclooxygenase-2 inhibitors (COX-2 inhibitors), also known as coxibs, are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly target cyclooxygenase-2 ( COX-2), an enzyme responsible for inflammation and pain. Targeting selectivit ...

down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in

levels as well as reducing proinflammatory cytokine activity. 1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase, but is also a very slow substrate. The specific racemer 1-methyl--tryptophan (known as indoximod) is in clinical trials for various cancers. Epacadostat (INCB24360), navoximod (GDC-0919), and

linrodostat Linrodostat (development code BMS-986205) is an experimental drug being studied for its immunomodulating and antineoplastic activities. Linrodostat is an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). Linrodostat has entered clinical tri ...

(BMS-986205) are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers.

References

External links

*
PDBe-KB
provides an overview of all the structure information available in the PDB for Human Indoleamine 2,3-dioxygenase 1 {{Portal bar, Biology, border=no EC 1.13.11 Immune system

Physiological function

Clinical significance

Inhibitors

See also

References

External links