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IDO1

Official Full Name
indoleamine 2,3-dioxygenase 1
Organism
Homo sapiens
GeneID
3620
Background
This gene encodes indoleamine 2,3-dioxygenase (IDO) - a heme enzyme that catalyzes the first and rate-limiting step in tryptophan catabolism to N-formyl-kynurenine. This enzyme acts on multiple tryptophan substrates including D-tryptophan, L-tryptophan, 5-hydroxy-tryptophan, tryptamine, and serotonin. This enzyme is thought to play a role in a variety of pathophysiological processes such as antimicrobial and antitumor defense, neuropathology, immunoregulation, and antioxidant activity. Through its expression in dendritic cells, monocytes, and macrophages this enzyme modulates T-cell behavior by its peri-cellular catabolization of the essential amino acid tryptophan.[provided by RefSeq, Feb 2011]
Synonyms
IDO; INDO; IDO-1;
Bio Chemical Class
Oxygenase
Protein Sequence
MAHAMENSWTISKEYHIDEEVGFALPNPQENLPDFYNDWMFIAKHLPDLIESGQLRERVEKLNMLSIDHLTDHKSQRLARLVLGCITMAYVWGKGHGDVRKVLPRNIAVPYCQLSKKLELPPILVYADCVLANWKKKDPNKPLTYENMDVLFSFRDGDCSKGFFLVSLLVEIAAASAIKVIPTVFKAMQMQERDTLLKALLEIASCLEKALQVFHQIHDHVNPKAFFSVLRIYLSGWKGNPQLSDGLVYEGFWEDPKEFAGGSAGQSSVFQCFDVLLGIQQTAGGGHAAQFLQDMRRYMPPAHRNFLCSLESNPSVREFVLSKGDAGLREAYDACVKALVSLRSYHLQIVTKYILIPASQQPKENKTSEDPSKLEAKGTGGTDLMNFLKTVRSTTEKSLLKEG
Open
Disease
Acute myeloid leukaemia, B-cell lymphoma, Brain cancer, Colorectal cancer, Depression, Head and neck cancer, Lung cancer, Lymphoma, Melanoma, Nasopharyngeal cancer, Neuroendocrine carcinoma, Ovarian cancer, Pancreatic cancer, Prostate cancer, Renal cell carcinoma, Solid tumour/cancer, Stomach cancer, Ureteral cancer
Approved Drug
1 +
Clinical Trial Drug
14 +
Discontinued Drug
0

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Detailed Information

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme crucial for the metabolism of tryptophan, an essential amino acid. Converting tryptophan into N-formyl-kynurenine, this enzyme drives the first and rate-limiting step of tryptophan breakdown in the kynurenine pathway. IDO1 participates in several physiological and pathological processes including immunological control, antimicrobial defense, and tumor immunity. Especially in the framework of immune system control and treatments, knowing IDO1's mechanism of action and how its inhibitors might affect disease processes is essential.

Structure and Function of IDO1

A heme-containing enzyme, IDO1 mostly runs in cells including monocytes, dendritic cells, and macrophages. By limiting the availability of tryptophan and modulating T-cell activity, it helps greatly in immunological tolerance. Specifically, IDO1 depletion of tryptophan restricts T-cell proliferation and causes the death of these immune cells. Tryptophan metabolite buildup also causes the development of regulatory T-cells, which support immunological balance maintenance and autoimmunity prevention.

Figure 1 illustrates the intracellular dynamics of IDO1 in dendritic cells, showing how IDO1 adapts its conformation and acquires functions based on the surrounding microenvironment.Figure 1. Intracellular dynamics of IDO1 in DCs. (Pallotta MT, et al., 2022)

The enzyme itself is made up of two primary structural domains: a large C-terminal domain (CTD) and a smaller N-terminal domain (NTD). With the heme group attaching to the C-terminal area, the CTD drives the catalytic activity of the enzyme. Acting as a cofactor to stabilize the enzyme and enable its catalytic activities, this heme group is essential for the enzyme's activity. Conversely, the NTD is engaged in signal transduction and has immune-receptor tyrosine inhibitory motifs (ITIMs), which help control immunological reactions.

Mechanism of Action

IDO1's catalytic cycle is initiated when it binds to the heme group containing Fe(3+) (ferric iron). The enzyme needs a lowering agent to lower the iron to Fe(2+) (ferrous iron), thereby becoming active. This decrease lets IDO1 interact with oxygen and tryptophan, hence producing a very reactive intermediate. This intermediate then drives tryptophan's conversion to N-formyl-kynurenine, a major metabolite in the kynurenine pathway. The enzyme returns to its lower state and prepares to start another cycle once this product is out.

This mechanism explains how IDO1 controls the balance between immune tolerance and activation, making it a target of great interest for diseases involving immune dysregulation, such as cancer and autoimmune disorders.

Role in Disease and Therapeutic Targeting

IDO1's participation in immunological regulation has generated great curiosity about its function in pathological conditions, particularly cancer. Tumors usually use the IDO1 route to reduce anti-tumor immunity. IDO1 inhibits the activation and proliferation of effector T-cells by depleting tryptophan in the tumor microenvironment, hence generating a more favorable environment for tumor survival and growth. IDO1 is therefore seen as an immunological checkpoint that inhibits anti-tumor reactions, therefore perhaps targeting it for immunotherapy.

Apart from its function in cancer, IDO1 is linked to various immune-related disorders. For example, altering immune responses at the maternal-fetal interface helps to shield the fetus from maternal immunological rejection throughout pregnancy. IDO1 has also been linked to certain infectious disorders since it starves them of tryptophan, an amino acid essential for their existence, hence inhibiting the growth of infections.

Inhibitors of IDO1: Development and Clinical Trials

Researchers have concentrated on creating IDO1 inhibitors to change its activity in disease therapy as it is so important for immune control. Based on their modes of action, these inhibitors are classified into numerous categories. L-1MT and other type I inhibitors are competitive ones that directly bind to the active site of the enzyme, therefore blocking its interaction with tryptophan. Like epacadostat, type II inhibitors bind to the enzyme's reduced form and block its interaction with oxygen, therefore limiting its catalytic activity. Other inhibitors, including 4PI, disrupt the enzyme's redox cycle, therefore preventing its activation.

Among the most researched IDO1 inhibitors, epacadostat is a selective one that has demonstrated promise in early-phase clinical trials and preclinical research. Clinical studies with epacadostat in conjunction with various immunotherapies, including checkpoint inhibitors, were stopped, however, despite early expectations, because of inadequate effectiveness. Linrodostat, another molecule, showed strong efficacy in preclinical research and was moving through clinical trials until 2018 when it was stopped. These disappointments draw attention to the difficulties in creating efficient IDO1 inhibitors for therapeutic application as the complicated control of the enzyme and the necessity for exact blockage in particular situations call for close attention.

Though their outcomes have varied, other inhibitors such as the tryptophan analogue indoximod and the quinoline-based molecule BMS-986205 have also begun clinical testing. For instance, Indoximod has multi-target effects and is not a very selective IDO1 inhibitor. Though its precise function and mechanism are still being studied, it has been tried in conjunction with immune checkpoint inhibitors for melanoma therapy.

Future Directions in IDO1 Inhibition

Recent developments in the structural knowledge of IDO1 and its interactions with inhibitors have provided new paths for pharmaceutical creation. Studies using crystallography have shown that numerous high-affinity inhibitors attach to the active site of the enzyme, filling areas A and B, which are essential for its activity. Researchers want to create inhibitors with more selectivity and lower off-target effects by more efficiently targeting these areas.

Furthermore, increasing popularity is the creation of dual-target inhibitors blocking both IDO1 and its associated enzyme TDO (tryptophan 2,3-dioxygenase). By reducing immunological tolerance and encouraging anti-tumor immunity, some drugs—like HTI-1090—show potential in treating cancer.

As research progresses, the focus will likely shift toward finding IDO1 inhibitors that can be used in combination therapies to enhance the efficacy of immunotherapies. Despite the challenges, the pursuit of effective IDO1 inhibition remains a promising strategy for treating a range of immune-related diseases, particularly cancer and autoimmune disorders.

References:

  1. XiFeng, Dongdong Liao, Dongyu Liu, et al. Development of Indoleamine2,3-Dioxygenase 1 Inhibitors for Cancer Therapy and Beyond: A RecentPerspective. J. Med. Chem. 2020, 63, 24, 15115–15139.
  2. UteF. Röhrig, Aline Reynaud, Somi Reddy Majjigapu, et al. Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1). J. Med. Chem. 2019, 62, 19,8784–8795.
  3. Pallotta MT, Rossini S, et al. Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme. FEBS J. 2022 Oct;289(20):6099-6118.
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