Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT91DBN7)

• DOT Name: Indoleamine 2,3-dioxygenase 1 (IDO1)
• Synonyms: IDO-1; EC 1.13.11.52; Indoleamine-pyrrole 2,3-dioxygenase
• Gene Name: IDO1
• UniProt ID: I23O1_HUMAN
• PDB ID: 2D0T ; 2D0U ; 4PK5 ; 4PK6 ; 4U72 ; 4U74 ; 5EK2 ; 5EK3 ; 5EK4 ; 5ETW ; 5WHR ; 5WMU ; 5WMV ; 5WMW ; 5WMX ; 5WN8 ; 5XE1 ; 6AZU ; 6AZV ; 6AZW ; 6CXU ; 6CXV ; 6DPQ ; 6DPR ; 6E35 ; 6E40 ; 6E41 ; 6E42 ; 6E43 ; 6E44 ; 6E45 ; 6E46 ; 6F0A ; 6KOF ; 6KPS ; 6KW7 ; 6MQ6 ; 6O3I ; 6PU7 ; 6PZ1 ; 6R63 ; 6UBP ; 6V52 ; 6WJY ; 6WPE ; 6X5Y ; 7A62 ; 7AH4 ; 7AH5 ; 7AH6 ; 7B1O ; 7E0O ; 7E0P ; 7E0Q ; 7E0S ; 7E0T ; 7E0U ; 7M63 ; 7M7D ; 7NGE ; 7P0N ; 7P0R ; 7RRB ; 7RRC ; 7RRD ; 7YXT ; 7Z2L ; 7ZV3 ; 8ABX ; 8FUR ; 8I7L
• EC Number: 1.13.11.52
• Pfam ID: PF01231
• Sequence:
  MAHAMENSWTISKEYHIDEEVGFALPNPQENLPDFYNDWMFIAKHLPDLIESGQLRERVE
  KLNMLSIDHLTDHKSQRLARLVLGCITMAYVWGKGHGDVRKVLPRNIAVPYCQLSKKLEL
  PPILVYADCVLANWKKKDPNKPLTYENMDVLFSFRDGDCSKGFFLVSLLVEIAAASAIKV
  IPTVFKAMQMQERDTLLKALLEIASCLEKALQVFHQIHDHVNPKAFFSVLRIYLSGWKGN
  PQLSDGLVYEGFWEDPKEFAGGSAGQSSVFQCFDVLLGIQQTAGGGHAAQFLQDMRRYMP
  PAHRNFLCSLESNPSVREFVLSKGDAGLREAYDACVKALVSLRSYHLQIVTKYILIPASQ
  QPKENKTSEDPSKLEAKGTGGTDLMNFLKTVRSTTEKSLLKEG
• Function: Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway. Involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses. Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells. Acts as a suppressor of anti-tumor immunity. Limits the growth of intracellular pathogens by depriving tryptophan. Protects the fetus from maternal immune rejection.
• Tissue Specificity: Expressed in mature dendritic cells located in lymphoid organs (including lymph nodes, spleen, tonsils, Peyers's patches, the gut lamina propria, and the thymic medulla), in some epithelial cells of the female genital tract, as well as in endothelial cells of term placenta and in lung parenchyma . Weakly or not expressed in most normal tissues, but mostly inducible in most tissues . Expressed in more than 50% of tumors, either by tumoral, stromal, or endothelial cells (expression in tumor is associated with a worse clinical outcome) . Not overexpressed in tumor-draining lymph nodes .
• KEGG Pathway:
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
  African trypanosomiasis (hsa05143)
• Reactome Pathway: Tryptophan catabolism (R-HSA-71240)
• BioCyc Pathway: MetaCyc:HS05502-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Indoleamine 2,3-dioxygenase 1 (IDO1) affects the response to substance of Aspirin.	[20]

19 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[3]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[9]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[10]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[11]
Aciclovir	DMYLOVR	Approved	Aciclovir decreases the activity of Indoleamine 2,3-dioxygenase 1 (IDO1).	[12]
L-tryptophan	DMIBH7M	Approved	L-tryptophan increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[14]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the activity of Indoleamine 2,3-dioxygenase 1 (IDO1).	[15]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[16]
INCB24360	DMIJGT9	Phase 3	INCB24360 decreases the activity of Indoleamine 2,3-dioxygenase 1 (IDO1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Indoleamine 2,3-dioxygenase 1 (IDO1).	[19]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [4] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] Oxidative stress modulates expression of immune checkpoint genes via activation of AhR signaling. Toxicol Appl Pharmacol. 2022 Dec 15;457:116314. doi: 10.1016/j.taap.2022.116314. Epub 2022 Nov 9.
• [7] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance. Clin Exp Immunol. 2010 Aug;161(2):298-305. doi: 10.1111/j.1365-2249.2010.04170.x. Epub 2010 May 18.
• [12] Mechanisms by which acyclovir reduces the oxidative neurotoxicity and biosynthesis of quinolinic acid. Life Sci. 2007 Feb 13;80(10):918-25.
• [13] Tryptophan and kynurenine stimulate human decidualization via activating Aryl hydrocarbon receptor: Short title: Kynurenine action on human decidualization. Reprod Toxicol. 2020 Sep;96:282-292. doi: 10.1016/j.reprotox.2020.07.011. Epub 2020 Aug 8.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Resveratrol suppresses interferon-gamma-induced biochemical pathways in human peripheral blood mononuclear cells in vitro. Immunol Lett. 2005 Sep 15;100(2):159-63. doi: 10.1016/j.imlet.2005.03.008. Epub 2005 Apr 7.
• [16] Curcumin downregulates H19 gene transcription in tumor cells. J Cell Biochem. 2008 Aug 1;104(5):1781-92.
• [17] Salinomycin promotes T-cell proliferation by inhibiting the expression and enzymatic activity of immunosuppressive indoleamine-2,3-dioxygenase in human breast cancer cells. Toxicol Appl Pharmacol. 2020 Oct 1;404:115203. doi: 10.1016/j.taap.2020.115203. Epub 2020 Aug 19.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma. Clin Exp Allergy. 2009 Jul;39(7):972-81. doi: 10.1111/j.1365-2222.2009.03229.x. Epub 2009 Mar 27.