Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX4EKES)

• DOT Name: Transmembrane protein 59 (TMEM59)
• Synonyms: Liver membrane-bound protein
• Gene Name: TMEM59
• Related Disease:
  Anxiety
  Anxiety disorder
  Bacterial infection
  Parkinson disease
  Staphylococcus aureus infection
  Advanced cancer
  Neuroblastoma
  Adult glioblastoma
  Glioblastoma multiforme
• UniProt ID: TMM59_HUMAN
• Pfam ID: PF12280
• Sequence:
  MAAPKGSLWVRTQLGLPPLLLLTMALAGGSGTASAEAFDSVLGDTASCHRACQLTYPLHT
  YPKEEELYACQRGCRLFSICQFVDDGIDLNRTKLECESACTEAYSQSDEQYACHLGCQNQ
  LPFAELRQEQLMSLMPKMHLLFPLTLVRSFWSDMMDSAQSFITSSWTFYLQADDGKIVIF
  QSKPEIQYAPHLEQEPTNLRESSLSKMSYLQMRNSQAHRNFLEDGESDGFLRCLSLNSGW
  ILTTTLVLSVMVLLWICCATVATAVEQYVPSEKLSIYGDLEFMNEQKLNRYPASSLVVVR
  SKTEDHEEAGPLPTKVNLAHSEI
• Function: Acts as a regulator of autophagy in response to S.aureus infection by promoting activation of LC3 (MAP1LC3A, MAP1LC3B or MAP1LC3C). Acts by interacting with ATG16L1, leading to promote a functional complex between LC3 and ATG16L1 and promoting LC3 lipidation and subsequent activation of autophagy. Modulates the O-glycosylation and complex N-glycosylation steps occurring during the Golgi maturation of several proteins such as APP, BACE1, SEAP or PRNP. Inhibits APP transport to the cell surface and further shedding.
• Reactome Pathway:
  RND1 GTPase cycle (R-HSA-9696273)
  RHOH GTPase cycle (R-HSA-9013407)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anxiety	DISIJDBA	Definitive	Biomarker	[1]
Anxiety disorder	DISBI2BT	Definitive	Biomarker	[1]
Bacterial infection	DIS5QJ9S	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Staphylococcus aureus infection	DISK6PTH	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[5]
Neuroblastoma	DISVZBI4	Disputed	Biomarker	[6]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Transmembrane protein 59 (TMEM59) affects the response to substance of Paclitaxel.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Transmembrane protein 59 (TMEM59).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the ubiquitination of Transmembrane protein 59 (TMEM59).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Transmembrane protein 59 (TMEM59).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transmembrane protein 59 (TMEM59).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Transmembrane protein 59 (TMEM59).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transmembrane protein 59 (TMEM59).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane protein 59 (TMEM59).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Transmembrane protein 59 (TMEM59).	[15]

References

• [1] Dcf1 Affects Memory and Anxiety by Regulating NMDA and AMPA Receptors.Neurochem Res. 2019 Nov;44(11):2499-2505. doi: 10.1007/s11064-019-02866-6. Epub 2019 Sep 17.
• [2] Unconventional autophagy mediated by the WD40 domain of ATG16L1 is derailed by the T300A Crohn disease risk polymorphism.Autophagy. 2016 Nov;12(11):2254-2255. doi: 10.1080/15548627.2016.1216303. Epub 2016 Aug 19.
• [3] Degradation of alpha-synuclein by dendritic cell factor 1 delays neurodegeneration and extends lifespan in Drosophila.Neurobiol Aging. 2018 Jul;67:67-74. doi: 10.1016/j.neurobiolaging.2018.03.010. Epub 2018 Mar 13.
• [4] TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3.EMBO J. 2013 Feb 20;32(4):566-82. doi: 10.1038/emboj.2013.8. Epub 2013 Feb 1.
• [5] Overexpression of DCF1 inhibits glioma through destruction of mitochondria and activation of apoptosis pathway.Sci Rep. 2014 Jan 15;4:3702. doi: 10.1038/srep03702.
• [6] Dendritic cell factor 1 inhibits proliferation and migration and induces apoptosis of neuroblastoma cells by inhibiting the ERK signaling pathway.Oncol Rep. 2019 Jan;41(1):103-112. doi: 10.3892/or.2018.6796. Epub 2018 Oct 16.
• [7] The antitumor effect of TAT-DCF1 peptide in glioma cells.Neuropeptides. 2018 Oct;71:21-31. doi: 10.1016/j.npep.2018.06.004. Epub 2018 Jun 25.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [13] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.