Details of Drug Off-Target (DOT)

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

• DOT Name: Torsin-1A (TOR1A)
• Synonyms: Dystonia 1 protein; Torsin ATPase-1A; EC 3.6.4.-; Torsin family 1 member A
• Gene Name: TOR1A
• Related Disease:
  Early-onset generalized limb-onset dystonia
  Arthrogryposis multiplex congenita 5
• UniProt ID: TOR1A_HUMAN
• PDB ID: 5J1S; 5J1T; 6OIF
• EC Number: 3.6.4.-
• Pfam ID: PF21376 ; PF06309
• Sequence:
  MKLGRAVLGLLLLAPSVVQAVEPISLGLALAGVLTGYIYPRLYCLFAECCGQKRSLSREA
  LQKDLDDNLFGQHLAKKIILNAVFGFINNPKPKKPLTLSLHGWTGTGKNFVSKIIAENIY
  EGGLNSDYVHLFVATLHFPHASNITLYKDQLQLWIRGNVSACARSIFIFDEMDKMHAGLI
  DAIKPFLDYYDLVDGVSYQKAMFIFLSNAGAERITDVALDFWRSGKQREDIKLKDIEHAL
  SVSVFNNKNSGFWHSSLIDRNLIDYFVPFLPLEYKHLKMCIRVEMQSRGYEIDEDIVSRV
  AEEMTFFPKEERVFSDKGCKTVFTKLDYYYDD
• Function: Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates. Involved in the regulation of synaptic vesicle recycling, controls STON2 protein stability in collaboration with the COP9 signalosome complex (CSN). In the nucleus, may link the cytoskeleton with the nuclear envelope, this mechanism seems to be crucial for the control of nuclear polarity, cell movement and, specifically in neurons, nuclear envelope integrity. Participates in the cellular trafficking and may regulate the subcellular location of multipass membrane proteins such as the dopamine transporter SLC6A3, leading to the modulation of dopamine neurotransmission. In the endoplasmic reticulum, plays a role in the quality control of protein folding by increasing clearance of misfolded proteins such as SGCE variants or holding them in an intermediate state for proper refolding. May have a redundant function with TOR1B in non-neural tissues.
• Tissue Specificity: Widely expressed. Highest levels in kidney and liver. In the brain, high levels found in the dopaminergic neurons of the substantia nigra pars compacta, as well as in the neocortex, hippocampus and cerebellum. Also highly expressed in the spinal cord.
• Reactome Pathway: Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Early-onset generalized limb-onset dystonia	DISDY57E	Definitive	Autosomal dominant	[1]
Arthrogryposis multiplex congenita 5	DIS37TLQ	Strong	Autosomal recessive	[2]

17 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 Torsin-1A (TOR1A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Torsin-1A (TOR1A).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Torsin-1A (TOR1A).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Torsin-1A (TOR1A).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Torsin-1A (TOR1A).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Torsin-1A (TOR1A).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Torsin-1A (TOR1A).	[9]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Torsin-1A (TOR1A).	[7]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Torsin-1A (TOR1A).	[7]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Torsin-1A (TOR1A).	[7]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Torsin-1A (TOR1A).	[7]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Torsin-1A (TOR1A).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Torsin-1A (TOR1A).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Torsin-1A (TOR1A).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Torsin-1A (TOR1A).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Torsin-1A (TOR1A).	[13]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Torsin-1A (TOR1A).	[14]

References

• [1] De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia. Hum Mol Genet. 1998 Jul;7(7):1133-6. doi: 10.1093/hmg/7.7.1133.
• [2] Dystonia and the nuclear envelope. Neuron. 2005 Dec 22;48(6):875-7. doi: 10.1016/j.neuron.2005.12.006.
• [3] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [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] 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.
• [10] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [11] 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.
• [12] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.