# IDO1

## Overview
IDO1, or indoleamine 2,3-dioxygenase 1, is a gene that encodes for the heme-containing enzyme indoleamine 2,3-dioxygenase 1. This enzyme is crucial in the catabolism of the amino acid tryptophan through the kynurenine pathway, playing a significant role in immune regulation and response to infection. IDO1 is expressed in various tissues, particularly within the immune system, where it modulates immune tolerance and inflammation through the degradation of tryptophan and the production of kynurenine metabolites. These metabolites can influence immune cell function and are involved in the suppression of T cell activity and the promotion of regulatory T cell development. The enzyme's activity is also essential in antimicrobial defense, highlighting its dual role in both immune regulation and pathogen resistance (Arefayene2009Identification; Niño-Castro2013The).

## Structure
The molecular structure of the IDO1 protein, encoded by the human gene IDO1, is characterized by its division into two distinct domains: a smaller N-terminal domain (NTD) and a larger C-terminal domain (CTD). The NTD is composed of six alpha-helices, two short beta-sheets, and three 3_10 helices, while the CTD consists of thirteen alpha-helices and two 3_10 helices (Lewis-Ballester2017Structural; Tang2021Indoleamine). These domains are connected by numerous hydrophobic interactions and salt bridges, contributing to the protein's tertiary structure (Tang2021Indoleamine).

The CTD of IDO1 is particularly notable for containing the active site, where the substrate tryptophan binds. This binding induces the transformation of part of the JK-Loop into a beta-hairpin structure, which is crucial for the enzyme's function (Lewis-Ballester2017Structural). The heme prosthetic group, essential for the enzyme's dioxygenase activity, is located between the NTD and CTD, with His346 playing a significant role in heme-protein interactions (Lancellotti2011Biochemical).

While the primary structure of IDO1 consists of 403 amino acids, details on post-translational modifications or splice variant isoforms are not specified in the provided contexts. Additionally, no information on quaternary structure is available from the given sources.

## Function
IDO1 (indoleamine 2,3-dioxygenase 1) is an enzyme that plays a pivotal role in the catabolism of the amino acid tryptophan through the kynurenine pathway, which is crucial for maintaining immune tolerance and regulating immune responses. This enzyme catalyzes the first and rate-limiting step in the conversion of tryptophan to N-formylkynurenine. IDO1 is widely expressed in both immune and non-immune tissues, including dendritic cells and macrophages, where it is induced upon exposure to interferons or infection with various pathogens such as bacteria, viruses, and parasites (Arefayene2009Identification; Niño-Castro2013The).

The activity of IDO1 leads to local depletion of tryptophan and an increase in kynurenine metabolites, which can suppress effector T cell function and promote the development of regulatory T cells. This suppression is achieved through mechanisms such as the induction of cell cycle arrest or apoptosis in T cells (Arefayene2009Identification; Merlo2020Differential). Additionally, the kynurenine pathway metabolites activate the aryl hydrocarbon receptor (AhR), influencing further immune regulation (Merlo2020Differential).

In the context of infections, IDO1's enzymatic activity is essential for antimicrobial defense, particularly against pathogens like Listeria monocytogenes, by producing metabolites that have direct antimicrobial properties (Niño-Castro2013The). This role highlights IDO1's importance not only in immune regulation but also in cellular defense mechanisms against infections.

## Clinical Significance
IDO1 (indoleamine 2,3-dioxygenase 1) gene mutations and alterations in expression have been linked to various diseases, highlighting its clinical significance. In Crohn's Disease (CD), genetic variants of IDO1 are associated with a more severe disease course, characterized by a higher likelihood of extraintestinal manifestations and a need for aggressive treatment (Lee2014IDO1). Similarly, in colorectal cancer (CRC), high IDO1 expression correlates with more aggressive cancer phenotypes and poorer clinical outcomes, suggesting its role in immune evasion by cancer cells (Chen2016Expression).

IDO1 also plays a crucial role in the immune response to infections. For instance, polymorphisms in IDO1 affect susceptibility to aspergillosis in patients with cystic fibrosis and recipients of hematopoietic stem cell transplantation, where reduced IDO1 function due to specific SNPs correlates with increased inflammatory responses (Napolioni2019Genetic). Additionally, IDO1 has been identified as a potential biomarker for diabetic nephropathy, with its expression levels significantly increased in this condition, correlating with immune cell infiltration and disease progression (Yu2021IDO1).

These findings underscore the importance of IDO1 in various pathological conditions and its potential as a target for therapeutic intervention.

## Interactions
IDO1 (indoleamine 2,3-dioxygenase 1) does not have documented interactions with other proteins or nucleic acids based on the provided excerpts. The research primarily focuses on the enzyme's interaction with small molecule inhibitors and its role in the immune system, particularly in the context of cancer immunology. The studies detailed involve the inhibition of IDO1 activity through various compounds, analyzing the enzyme's binding with these inhibitors and the subsequent effects on immune cell function and tumor growth. For instance, specific amino acids such as Ser167 are crucial for the binding of inhibitors to IDO1, affecting the enzyme's activity and its role in immune suppression (Tomek2017Discovery). However, these interactions are limited to the enzyme's relationship with inhibitors and do not extend to interactions with other proteins or nucleic acids. Therefore, based on the available information, it is not possible to describe multiprotein complexes or transitory interactions involving IDO1 with other proteins or nucleic acids.


## References


[1. (Lewis-Ballester2017Structural) Ariel Lewis-Ballester, Khoa N. Pham, Dipanwita Batabyal, Shay Karkashon, Jeffrey B. Bonanno, Thomas L. Poulos, and Syun-Ru Yeh. Structural insights into substrate and inhibitor binding sites in human indoleamine 2,3-dioxygenase 1. Nature Communications, November 2017. URL: http://dx.doi.org/10.1038/s41467-017-01725-8, doi:10.1038/s41467-017-01725-8. (127 citations) 10.1038/s41467-017-01725-8](https://doi.org/10.1038/s41467-017-01725-8)

[2. (Merlo2020Differential) Lauren M. F. Merlo, James B. DuHadaway, James D. Montgomery, Wei-Dan Peng, Peter J. Murray, George C. Prendergast, Andrew J. Caton, Alexander J. Muller, and Laura Mandik-Nayak. Differential roles of ido1 and ido2 in t and b cell inflammatory immune responses. Frontiers in Immunology, August 2020. URL: http://dx.doi.org/10.3389/fimmu.2020.01861, doi:10.3389/fimmu.2020.01861. (84 citations) 10.3389/fimmu.2020.01861](https://doi.org/10.3389/fimmu.2020.01861)

[3. (Lee2014IDO1) Alexander Lee, Navya Kanuri, Yuanhao Zhang, Gregory S. Sayuk, Ellen Li, and Matthew A. Ciorba. Ido1 and ido2 non-synonymous gene variants: correlation with crohn’s disease risk and clinical phenotype. PLoS ONE, 9(12):e115848, December 2014. URL: http://dx.doi.org/10.1371/journal.pone.0115848, doi:10.1371/journal.pone.0115848. (33 citations) 10.1371/journal.pone.0115848](https://doi.org/10.1371/journal.pone.0115848)

[4. (Lancellotti2011Biochemical) S. Lancellotti, L. Novarese, and R. De Cristofaro. Biochemical properties of indoleamine 2,3-dioxygenase: from structure to optimized design of inhibitors. Current Medicinal Chemistry, 18(15):2205–2214, May 2011. URL: http://dx.doi.org/10.2174/092986711795656108, doi:10.2174/092986711795656108. (31 citations) 10.2174/092986711795656108](https://doi.org/10.2174/092986711795656108)

[5. (Tomek2017Discovery) Petr Tomek, Brian D. Palmer, Jack U. Flanagan, Chuanwen Sun, Emma L. Raven, and Lai-Ming Ching. Discovery and evaluation of inhibitors to the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (ido1): probing the active site-inhibitor interactions. European Journal of Medicinal Chemistry, 126:983–996, January 2017. URL: http://dx.doi.org/10.1016/j.ejmech.2016.12.029, doi:10.1016/j.ejmech.2016.12.029. (35 citations) 10.1016/j.ejmech.2016.12.029](https://doi.org/10.1016/j.ejmech.2016.12.029)

[6. (Yu2021IDO1) Kuipeng Yu, Dengren Li, Fuping Xu, Hao Guo, Feng Feng, Yu Ding, Xiang Wan, Nan Sun, Yang Zhang, Jiahui Fan, Lei Liu, Huimin Yang, and Xiangdong Yang. Ido1 as a new immune biomarker for diabetic nephropathy and its correlation with immune cell infiltration. International Immunopharmacology, 94:107446, May 2021. URL: http://dx.doi.org/10.1016/j.intimp.2021.107446, doi:10.1016/j.intimp.2021.107446. (19 citations) 10.1016/j.intimp.2021.107446](https://doi.org/10.1016/j.intimp.2021.107446)

[7. (Arefayene2009Identification) Million Arefayene, Santosh Philips, Donghua Cao, Sudharani Mamidipalli, Zeruesenay Desta, David A. Flockhart, David S. Wilkes, and Todd C. Skaar. Identification of genetic variants in the human indoleamine 2,3-dioxygenase (ido1) gene, which have altered enzyme activity. Pharmacogenetics and Genomics, 19(6):464–476, June 2009. URL: http://dx.doi.org/10.1097/fpc.0b013e32832c005a, doi:10.1097/fpc.0b013e32832c005a. (42 citations) 10.1097/fpc.0b013e32832c005a](https://doi.org/10.1097/fpc.0b013e32832c005a)

[8. (Chen2016Expression) I-Chien Chen, Kuen-Haur Lee, Ying-Hua Hsu, Wei-Ran Wang, Chuan-Mu Chen, and Ya-Wen Cheng. Expression pattern and clinicopathological relevance of the indoleamine 2,3-dioxygenase 1/tryptophan 2,3-dioxygenase protein in colorectal cancer. Disease Markers, 2016:1–9, 2016. URL: http://dx.doi.org/10.1155/2016/8169724, doi:10.1155/2016/8169724. (37 citations) 10.1155/2016/8169724](https://doi.org/10.1155/2016/8169724)

[9. (Tang2021Indoleamine) Kai Tang, Ya-Hong Wu, Yihui Song, and Bin Yu. Indoleamine 2,3-dioxygenase 1 (ido1) inhibitors in clinical trials for cancer immunotherapy. Journal of Hematology & Oncology, April 2021. URL: http://dx.doi.org/10.1186/s13045-021-01080-8, doi:10.1186/s13045-021-01080-8. (192 citations) 10.1186/s13045-021-01080-8](https://doi.org/10.1186/s13045-021-01080-8)

[10. (Niño-Castro2013The) Andrea Niño-Castro, Zeinab Abdullah, Alexey Popov, Yasser Thabet, Marc Beyer, Percy Knolle, Eugen Domann, Trinad Chakraborty, Susanne V Schmidt, and Joachim L Schultze. The ido1-induced kynurenines play a major role in the antimicrobial effect of human myeloid cells againstlisteria monocytogenes. Innate Immunity, 20(4):401–411, August 2013. URL: http://dx.doi.org/10.1177/1753425913496442, doi:10.1177/1753425913496442. (51 citations) 10.1177/1753425913496442](https://doi.org/10.1177/1753425913496442)

[11. (Napolioni2019Genetic) Valerio Napolioni, Marilena Pariano, Monica Borghi, Vasilis Oikonomou, Claudia Galosi, Antonella De Luca, Claudia Stincardini, Carmine Vacca, Giorgia Renga, Vincenzina Lucidi, Carla Colombo, Ersilia Fiscarelli, Cornelia Lass-Flörl, Alessandra Carotti, Lucia D’Amico, Fabio Majo, Maria Chiara Russo, Helmut Ellemunter, Angelica Spolzino, Paolo Mosci, Stefano Brancorsini, Franco Aversa, Andrea Velardi, Luigina Romani, and Claudio Costantini. Genetic polymorphisms affecting ido1 or ido2 activity differently associate with aspergillosis in humans. Frontiers in Immunology, May 2019. URL: http://dx.doi.org/10.3389/fimmu.2019.00890, doi:10.3389/fimmu.2019.00890. (18 citations) 10.3389/fimmu.2019.00890](https://doi.org/10.3389/fimmu.2019.00890)