Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW0B0KS)

• DOT Name: Transmembrane protein 41B (TMEM41B)
• Synonyms: Protein stasimon
• Gene Name: TMEM41B
• Related Disease:
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Spinal muscular atrophy
• UniProt ID: TM41B_HUMAN
• Pfam ID: PF09335
• Sequence:
  MAKGRVAERSQLGAHHTTPVGDGAAGTRGLAAPGSRDHQKEKSWVEAGSARMSLLILVSI
  FLSAAFVMFLVYKNFPQLSEEERVNMKVPRDMDDAKALGKVLSKYKDTFYVQVLVAYFAT
  YIFLQTFAIPGSIFLSILSGFLYPFPLALFLVCLCSGLGASFCYMLSYLVGRPVVYKYLT
  EKAVKWSQQVERHREHLINYIIFLRITPFLPNWFINITSPVINVPLKVFFIGTFLGVAPP
  SFVAIKAGTTLYQLTTAGEAVSWNSIFILMILAVLSILPAIFQKKLKQKFE
• Function: Phospholipid scramblase involved in lipid homeostasis and membrane dynamics processes. Has phospholipid scramblase activity toward cholesterol and phosphatidylserine, as well as phosphatidylethanolamine and phosphatidylcholine. Required for autophagosome formation: participates in early stages of autophagosome biogenesis at the endoplasmic reticulum (ER) membrane by reequilibrating the leaflets of the ER as lipids are extracted by ATG2 (ATG2A or ATG2B) to mediate autophagosome assembly. In addition to autophagy, involved in other processes in which phospholipid scramblase activity is required. Required for normal motor neuron development; (Microbial infection) Critical host factor required for infection by human coronaviruses SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, as well as all flaviviruses tested such as Zika virus and Yellow fever virus. Required post-entry of the virus to facilitate the ER membrane remodeling necessary to form replication organelles.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[2]

11 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 Transmembrane protein 41B (TMEM41B).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Transmembrane protein 41B (TMEM41B).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transmembrane protein 41B (TMEM41B).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transmembrane protein 41B (TMEM41B).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transmembrane protein 41B (TMEM41B).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Transmembrane protein 41B (TMEM41B).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Transmembrane protein 41B (TMEM41B).	[9]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Transmembrane protein 41B (TMEM41B).	[10]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Transmembrane protein 41B (TMEM41B).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transmembrane protein 41B (TMEM41B).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transmembrane protein 41B (TMEM41B).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transmembrane protein 41B (TMEM41B).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Transmembrane protein 41B (TMEM41B).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transmembrane protein 41B (TMEM41B).	[16]

References

• [1] Cross-Kingdom Gene regulation via miRNAs of Hypericum perforatum (St. John's wort) flower dietetically absorbed: An in silico approach to define potential biomarkers for prostate cancer.Comput Biol Chem. 2019 Jun;80:16-22. doi: 10.1016/j.compbiolchem.2019.02.010. Epub 2019 Feb 28.
• [2] Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy.Cell Rep. 2019 Dec 17;29(12):3885-3901.e5. doi: 10.1016/j.celrep.2019.11.058.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [11] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] 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.
• [15] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [16] 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.