Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOX2872)

• DOT Name: Adenosine deaminase (ADA)
• Synonyms: EC 3.5.4.4; Adenosine aminohydrolase
• Gene Name: ADA
• Related Disease:
  Adenosine deaminase defciency
  Omenn syndrome
• UniProt ID: ADA_HUMAN
• PDB ID: 3IAR; 7RTG
• EC Number: 3.5.4.4
• Pfam ID: PF00962
• Sequence:
  MAQTPAFDKPKVELHVHLDGSIKPETILYYGRRRGIALPANTAEGLLNVIGMDKPLTLPD
  FLAKFDYYMPAIAGCREAIKRIAYEFVEMKAKEGVVYVEVRYSPHLLANSKVEPIPWNQA
  EGDLTPDEVVALVGQGLQEGERDFGVKARSILCCMRHQPNWSPKVVELCKKYQQQTVVAI
  DLAGDETIPGSSLLPGHVQAYQEAVKSGIHRTVHAGEVGSAEVVKEAVDILKTERLGHGY
  HTLEDQALYNRLRQENMHFEICPWSSYLTGAWKPDTEHAVIRLKNDQANYSLNTDDPLIF
  KSTLDTDYQMTKRDMGFTEEEFKRLNINAAKSSFLPEDEKRELLDLLYKAYGMPPSASAG
  QNL
• Function: Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine. Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion. Enhances dendritic cell immunogenicity by affecting dendritic cell costimulatory molecule expression and cytokines and chemokines secretion. Enhances CD4+ T-cell differentiation and proliferation. Acts as a positive modulator of adenosine receptors ADORA1 and ADORA2A, by enhancing their ligand affinity via conformational change. Stimulates plasminogen activation. Plays a role in male fertility. Plays a protective role in early postimplantation embryonic development.
• Tissue Specificity: Found in all tissues, occurs in large amounts in T-lymphocytes . Expressed at the time of weaning in gastrointestinal tissues.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Defective ADA disrupts (deoxy)adenosine deamination (R-HSA-9734735)
  Ribavirin ADME (R-HSA-9755088)
  Purine salvage (R-HSA-74217)
• BioCyc Pathway: MetaCyc:HS02191-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenosine deaminase defciency	DISC2C93	Definitive	Autosomal recessive	[1]
Omenn syndrome	DIS2C887	Supportive	Autosomal recessive	[2]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Inosine	DMY65AR	Investigative	Adenosine deaminase (ADA) decreases the abundance of Inosine.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Adenosine deaminase (ADA).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Adenosine deaminase (ADA).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Adenosine deaminase (ADA).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adenosine deaminase (ADA).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adenosine deaminase (ADA).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Adenosine deaminase (ADA).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Adenosine deaminase (ADA).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Adenosine deaminase (ADA).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Adenosine deaminase (ADA).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Adenosine deaminase (ADA).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Adenosine deaminase (ADA).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Adenosine deaminase (ADA).	[15]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Adenosine deaminase (ADA).	[16]
Corticotropin	DMP9TWZ	Approved	Corticotropin increases the activity of Adenosine deaminase (ADA).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Adenosine deaminase (ADA).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Adenosine deaminase (ADA).	[5]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Adenosine deaminase (ADA).	[13]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Adenosine deaminase (ADA).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Adenosine deaminase (ADA).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Adenosine deaminase (ADA).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Adenosine deaminase (ADA).	[22]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Adenosine deaminase (ADA).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Adenosine deaminase (ADA).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Adenosine deaminase (ADA).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Adenosine deaminase (ADA).	[24]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Adenosine deaminase (ADA).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Adenosine deaminase (ADA).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] 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.
• [11] Proteomic analysis revealed association of aberrant ROS signaling with suberoylanilide hydroxamic acid-induced autophagy in Jurkat T-leukemia cells. Autophagy. 2010 Aug;6(6):711-24. doi: 10.4161/auto.6.6.12397. Epub 2010 Aug 17.
• [12] 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.
• [13] 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.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [16] Enhancement of erythrocytic adenosine deaminase following treatment of AIDS-related complex/AIDS patients with zidovudine. AIDS. 1990 Aug;4(8):799-802. doi: 10.1097/00002030-199008000-00012.
• [17] Activity of adenosine deaminase in red blood cells of patients suffering from multiple sclerosis treated with adrenocorticotropic hormone. Pol J Pharmacol. 1995 Nov-Dec;47(6):525-30.
• [18] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [19] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [20] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [21] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [25] A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15676-81.