Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMKZ4PV)

• DOT Name: BOS complex subunit TMEM147 (TMEM147)
• Synonyms: Protein NIFIE 14; Transmembrane protein 147
• Gene Name: TMEM147
• Related Disease:
  Arthritis
  Colon cancer
  Colon carcinoma
  Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly
  Rheumatoid arthritis
  Complex neurodevelopmental disorder
• UniProt ID: TM147_HUMAN
• PDB ID: 6W6L
• Pfam ID: PF09767
• Sequence:
  MTLFHFGNCFALAYFPYFITYKCSGLSEYNAFWKCVQAGVTYLFVQLCKMLFLATFFPTW
  EGGIYDFIGEFMKASVDVADLIGLNLVMSRNAGKGEYKIMVAALGWATAELIMSRCIPLW
  VGARGIEFDWKYIQMSIDSNISLVHYIVASAQVWMITRYDLYHTFRPAVLLLMFLSVYKA
  FVMETFVHLCSLGSWAALLARAVVTGLLALSTLALYVAVVNVHS
• Function: Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes. The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions. Also acts as a negative regulator of CHRM3 function, most likely by interfering with its trafficking to the cell membrane. Negatively regulates CHRM3-mediated calcium mobilization and activation of RPS6KA1/p90RSK activity. Regulates LBR localization to the nucleus inner membrane.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly	DISE7FZJ	Strong	Autosomal recessive	[3]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[1]
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal recessive	[4]

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 BOS complex subunit TMEM147 (TMEM147).	[5]

6 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 BOS complex subunit TMEM147 (TMEM147).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of BOS complex subunit TMEM147 (TMEM147).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BOS complex subunit TMEM147 (TMEM147).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of BOS complex subunit TMEM147 (TMEM147).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of BOS complex subunit TMEM147 (TMEM147).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of BOS complex subunit TMEM147 (TMEM147).	[11]

References

• [1] Role of Chondrocytes in the Development of Rheumatoid Arthritis Via Transmembrane Protein 147-Mediated NF-B Activation.Arthritis Rheumatol. 2020 Jun;72(6):931-942. doi: 10.1002/art.41182. Epub 2020 May 2.
• [2] Identification of specific modules and significant genes associated with colon cancer by weighted gene coexpression network analysis.Mol Med Rep. 2019 Jul;20(1):693-700. doi: 10.3892/mmr.2019.10295. Epub 2019 May 24.
• [3] Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. JAMA Psychiatry. 2017 Mar 1;74(3):293-299. doi: 10.1001/jamapsychiatry.2016.3798.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.