Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJL27PW)

• DOT Name: Antigen peptide transporter 1 (TAP1)
• Synonyms: APT1; EC 7.4.2.14; ATP-binding cassette sub-family B member 2; Peptide supply factor 1; Peptide transporter PSF1; PSF-1; Peptide transporter TAP1; Peptide transporter involved in antigen processing 1; Really interesting new gene 4 protein; RING4
• Gene Name: TAP1
• Related Disease: MHC class I deficiency
• UniProt ID: TAP1_HUMAN
• PDB ID: 1JJ7; 5U1D
• EC Number: 7.4.2.14
• Pfam ID: PF00664 ; PF00005
• Sequence:
  MASSRCPAPRGCRCLPGASLAWLGTVLLLLADWVLLRTALPRIFSLLVPTALPLLRVWAV
  GLSRWAVLWLGACGVLRATVGSKSENAGAQGWLAALKPLAAALGLALPGLALFRELISWG
  APGSADSTRLLHWGSHPTAFVVSYAAALPAAALWHKLGSLWVPGGQGGSGNPVRRLLGCL
  GSETRRLSLFLVLVVLSSLGEMAIPFFTGRLTDWILQDGSADTFTRNLTLMSILTIASAV
  LEFVGDGIYNNTMGHVHSHLQGEVFGAVLRQETEFFQQNQTGNIMSRVTEDTSTLSDSLS
  ENLSLFLWYLVRGLCLLGIMLWGSVSLTMVTLITLPLLFLLPKKVGKWYQLLEVQVRESL
  AKSSQVAIEALSAMPTVRSFANEEGEAQKFREKLQEIKTLNQKEAVAYAVNSWTTSISGM
  LLKVGILYIGGQLVTSGAVSSGNLVTFVLYQMQFTQAVEVLLSIYPRVQKAVGSSEKIFE
  YLDRTPRCPPSGLLTPLHLEGLVQFQDVSFAYPNRPDVLVLQGLTFTLRPGEVTALVGPN
  GSGKSTVAALLQNLYQPTGGQLLLDGKPLPQYEHRYLHRQVAAVGQEPQVFGRSLQENIA
  YGLTQKPTMEEITAAAVKSGAHSFISGLPQGYDTEVDEAGSQLSGGQRQAVALARALIRK
  PCVLILDDATSALDANSQLQVEQLLYESPERYSRSVLLITQHLSLVEQADHILFLEGGAI
  REGGTHQQLMEKKGCYWAMVQAPADAPE
• Function: ABC transporter associated with antigen processing. In complex with TAP2 mediates unidirectional translocation of peptide antigens from cytosol to endoplasmic reticulum (ER) for loading onto MHC class I (MHCI) molecules. Uses the chemical energy of ATP to export peptides against the concentration gradient. During the transport cycle alternates between 'inward-facing' state with peptide binding site facing the cytosol to 'outward-facing' state with peptide binding site facing the ER lumen. Peptide antigen binding to ATP-loaded TAP1-TAP2 induces a switch to hydrolysis-competent 'outward-facing' conformation ready for peptide loading onto nascent MHCI molecules. Subsequently ATP hydrolysis resets the transporter to the 'inward facing' state for a new cycle. Typically transports intracellular peptide antigens of 8 to 13 amino acids that arise from cytosolic proteolysis via IFNG-induced immunoproteasome. Binds peptides with free N- and C-termini, the first three and the C-terminal residues being critical. Preferentially selects peptides having a highly hydrophobic residue at position 3 and hydrophobic or charged residues at the C-terminal anchor. Proline at position 2 has the most destabilizing effect. As a component of the peptide loading complex (PLC), acts as a molecular scaffold essential for peptide-MHCI assembly and antigen presentation.
• Tissue Specificity: Highly expressed in professional APCs monocytes and dendritic cells as well as in lymphocyte subsets T cells, B cells and NK cells.
• KEGG Pathway:
  ABC transporters (hsa02010)
  Phagosome (hsa04145)
  Antigen processing and presentation (hsa04612)
  Human cytomegalovirus infection (hsa05163)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Antigen Presentation (R-HSA-983170)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
MHC class I deficiency	DISSMWCT	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Antigen peptide transporter 1 (TAP1) affects the response to substance of Mitoxantrone.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Antigen peptide transporter 1 (TAP1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Antigen peptide transporter 1 (TAP1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Antigen peptide transporter 1 (TAP1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Antigen peptide transporter 1 (TAP1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Antigen peptide transporter 1 (TAP1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Antigen peptide transporter 1 (TAP1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Antigen peptide transporter 1 (TAP1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Antigen peptide transporter 1 (TAP1).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Antigen peptide transporter 1 (TAP1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Antigen peptide transporter 1 (TAP1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Antigen peptide transporter 1 (TAP1).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Antigen peptide transporter 1 (TAP1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Antigen peptide transporter 1 (TAP1).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Antigen peptide transporter 1 (TAP1).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Antigen peptide transporter 1 (TAP1).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Antigen peptide transporter 1 (TAP1).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Antigen peptide transporter 1 (TAP1).	[18]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Antigen peptide transporter 1 (TAP1).	[19]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Antigen peptide transporter 1 (TAP1).	[20]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Antigen peptide transporter 1 (TAP1).	[21]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Antigen peptide transporter 1 (TAP1).	[19]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Antigen peptide transporter 1 (TAP1).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Antigen peptide transporter 1 (TAP1).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Antigen peptide transporter 1 (TAP1).	[4]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Antigen peptide transporter 1 (TAP1).	[19]
HMPL-004	DM29XGY	Phase 3	HMPL-004 increases the expression of Antigen peptide transporter 1 (TAP1).	[22]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl increases the expression of Antigen peptide transporter 1 (TAP1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Antigen peptide transporter 1 (TAP1).	[3]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Antigen peptide transporter 1 (TAP1).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Antigen peptide transporter 1 (TAP1).	[22]
2-tert-butylbenzene-1,4-diol	DMNXI1E	Investigative	2-tert-butylbenzene-1,4-diol increases the expression of Antigen peptide transporter 1 (TAP1).	[22]

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] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [7] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Combined effects of arsenic and palmitic acid on oxidative stress and lipid metabolism disorder in human hepatoma HepG2 cells. Sci Total Environ. 2021 May 15;769:144849. doi: 10.1016/j.scitotenv.2020.144849. Epub 2021 Jan 19.
• [10] 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.
• [11] 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.
• [12] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [17] Apoptosis, cell cycle progression and gene expression in TP53-depleted HCT116 colon cancer cells in response to short-term 5-fluorouracil treatment. Int J Oncol. 2007 Dec;31(6):1491-500.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [20] Evaluation of drug transporters' significance for multidrug resistance in head and neck squamous cell carcinoma. Head Neck. 2011 Jul;33(7):959-68. doi: 10.1002/hed.21559. Epub 2010 Aug 24.
• [21] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [22] Mapping the dynamics of Nrf2 antioxidant and NFB inflammatory responses by soft electrophilic chemicals in human liver cells defines the transition from adaptive to adverse responses. Toxicol In Vitro. 2022 Oct;84:105419. doi: 10.1016/j.tiv.2022.105419. Epub 2022 Jun 17.
• [23] Gene expressions associated with chemosensitivity in human hepatoma cells. Hepatogastroenterology. 2007 Mar;54(74):489-92.