Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK6Y1HK)

• DOT Name: TIR domain-containing adapter molecule 1 (TICAM1)
• Synonyms: TICAM-1; Proline-rich, vinculin and TIR domain-containing protein B; Putative NF-kappa-B-activating protein 502H; Toll-interleukin-1 receptor domain-containing adapter protein inducing interferon beta; MyD88-3; TIR domain-containing adapter protein inducing IFN-beta
• Gene Name: TICAM1
• Related Disease: Herpes simplex encephalitis, susceptibility to, 4
• UniProt ID: TCAM1_HUMAN
• PDB ID: 2M1X; 2M63; 3RC4; 4BSX; 4C0M; 5JEL
• Pfam ID: PF12721 ; PF17798
• Sequence:
  MACTGPSLPSAFDILGAAGQDKLLYLKHKLKTPRPGCQGQDLLHAMVLLKLGQETEARIS
  LEALKADAVARLVARQWAGVDSTEDPEEPPDVSWAVARLYHLLAEEKLCPASLRDVAYQE
  AVRTLSSRDDHRLGELQDEARNRCGWDIAGDPGSIRTLQSNLGCLPPSSALPSGTRSLPR
  PIDGVSDWSQGCSLRSTGSPASLASNLEISQSPTMPFLSLHRSPHGPSKLCDDPQASLVP
  EPVPGGCQEPEEMSWPPSGEIASPPELPSSPPPGLPEVAPDATSTGLPDTPAAPETSTNY
  PVECTEGSAGPQSLPLPILEPVKNPCSVKDQTPLQLSVEDTTSPNTKPCPPTPTTPETSP
  PPPPPPPSSTPCSAHLTPSSLFPSSLESSSEQKFYNFVILHARADEHIALRVREKLEALG
  VPDGATFCEDFQVPGRGELSCLQDAIDHSAFIILLLTSNFDCRLSLHQVNQAMMSNLTRQ
  GSPDCVIPFLPLESSPAQLSSDTASLLSGLVRLDEHSQIFARKVANTFKPHRLQARKAMW
  RKEQDTRALREQSQHLDGERMQAAALNAAYSAYLQSYLSYQAQMEQLQVAFGSHMSFGTG
  APYGARMPFGGQVPLGAPPPFPTWPGCPQPPPLHAWQAGTPPPPSPQPAAFPQSLPFPQS
  PAFPTASPAPPQSPGLQPLIIHHAQMVQLGLNNHMWNQRGSQAPEDKTQEAE
• Function: Involved in innate immunity against invading pathogens. Adapter used by TLR3, TLR4 (through TICAM2) and TLR5 to mediate NF-kappa-B and interferon-regulatory factor (IRF) activation, and to induce apoptosis. Ligand binding to these receptors results in TRIF recruitment through its TIR domain. Distinct protein-interaction motifs allow recruitment of the effector proteins TBK1, TRAF6 and RIPK1, which in turn, lead to the activation of transcription factors IRF3 and IRF7, NF-kappa-B and FADD respectively. Phosphorylation by TBK1 on the pLxIS motif leads to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent immunity against invading pathogens. Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines.
• Tissue Specificity: Ubiquitously expressed but with higher levels in liver.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Necroptosis (hsa04217)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  Alcoholic liver disease (hsa04936)
  Pertussis (hsa05133)
  Yersinia infection (hsa05135)
  Chagas disease (hsa05142)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  MyD88-independent TLR4 cascade (R-HSA-166166)
  Toll Like Receptor 3 (TLR3) Cascade (R-HSA-168164)
  TICAM1, RIP1-mediated IKK complex recruitment (R-HSA-168927)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  TRIF-mediated programmed cell death (R-HSA-2562578)
  TICAM1 deficiency - HSE (R-HSA-5602566)
  TRAF3 deficiency - HSE (R-HSA-5602571)
  TLR3-mediated TICAM1-dependent programmed cell death (R-HSA-9013957)
  TICAM1-dependent activation of IRF3/IRF7 (R-HSA-9013973)
  TICAM1,TRAF6-dependent induction of TAK1 complex (R-HSA-9014325)
  Activation of IRF3, IRF7 mediated by TBK1, IKK (IKBKE) (R-HSA-936964)
  IKK complex recruitment mediated by RIP1 (R-HSA-937041)
  TRAF6-mediated induction of TAK1 complex within TLR4 complex (R-HSA-937072)
  IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (R-HSA-975163)
  Caspase activation via Death Receptors in the presence of ligand (R-HSA-140534)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Herpes simplex encephalitis, susceptibility to, 4	DISGXN3Z	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of TIR domain-containing adapter molecule 1 (TICAM1).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[12]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of TIR domain-containing adapter molecule 1 (TICAM1).	[13]

References

• [1] Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood. J Pediatr. 2010 Oct;157(4):623-9, 629.e1. doi: 10.1016/j.jpeds.2010.04.020. Epub 2010 May 31.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] TLR2 and TLR3 expression as a biomarker for the risk of doxorubicin-induced heart failure. Toxicol Lett. 2018 Oct 1;295:205-211. doi: 10.1016/j.toxlet.2018.06.1219. Epub 2018 Jun 28.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [7] 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.
• [8] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.