Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY2H39E)

• DOT Name: ER membrane protein complex subunit 3 (EMC3)
• Synonyms: Transmembrane protein 111
• Gene Name: EMC3
• Related Disease:
  Familial hypertrophic cardiomyopathy
  Leigh syndrome
  Matthew-Wood syndrome
  Yellow fever virus infection
  Acute myelogenous leukaemia
  Leprosy
  Tuberculosis
• UniProt ID: EMC3_HUMAN
• PDB ID: 6WW7; 6Z3W; 7ADO; 7ADP; 8EOI; 8S9S
• Pfam ID: PF01956
• Sequence:
  MAGPELLLDSNIRLWVVLPIVIITFFVGMIRHYVSILLQSDKKLTQEQVSDSQVLIRSRV
  LRENGKYIPKQSFLTRKYYFNNPEDGFFKKTKRKVVPPSPMTDPTMLTDMMKGNVTNVLP
  MILIGGWINMTFSGFVTTKVPFPLTLRFKPMLQQGIELLTLDASWVSSASWYFLNVFGLR
  SIYSLILGQDNAADQSRMMQEQMTGAAMAMPADTNKAFKTEWEALELTDHQWALDDVEEE
  LMAKDLHFEGMFKKELQTSIF
• Function: Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues. Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices. It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes. By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors. By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes (Probable).
• Reactome Pathway: RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hypertrophic cardiomyopathy	DISQ89HN	Strong	Genetic Variation	[1]
Leigh syndrome	DISWQU45	Strong	Biomarker	[2]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[3]
Yellow fever virus infection	DISK0X5T	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[5]
Leprosy	DISAA4UI	Limited	Biomarker	[6]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[6]

9 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 ER membrane protein complex subunit 3 (EMC3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ER membrane protein complex subunit 3 (EMC3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ER membrane protein complex subunit 3 (EMC3).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ER membrane protein complex subunit 3 (EMC3).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ER membrane protein complex subunit 3 (EMC3).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ER membrane protein complex subunit 3 (EMC3).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of ER membrane protein complex subunit 3 (EMC3).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ER membrane protein complex subunit 3 (EMC3).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ER membrane protein complex subunit 3 (EMC3).	[15]

References

• [1] Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice.Nat Med. 2003 Dec;9(12):1477-83. doi: 10.1038/nm955. Epub 2003 Nov 2.
• [2] Expression and functional analysis of SURF1 in Leigh syndrome patients with cytochrome c oxidase deficiency.Hum Mol Genet. 1999 Dec;8(13):2541-9. doi: 10.1093/hmg/8.13.2541.
• [3] Perioperative cancer cell dissemination detected with a real-time RT-PCR assay for EpCAM is not associated with worse prognosis in pancreatic ductal adenocarcinoma.BMC Cancer. 2011 Jan 31;11:47. doi: 10.1186/1471-2407-11-47.
• [4] Dual roles for the ER membrane protein complex in flavivirus infection: viral entry and protein biogenesis.Sci Rep. 2019 Jul 4;9(1):9711. doi: 10.1038/s41598-019-45910-9.
• [5] A dominant-negative mutant of C/EBPalpha, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse.Blood. 2004 Apr 1;103(7):2744-52. doi: 10.1182/blood-2003-07-2280. Epub 2003 Dec 4.
• [6] Immunostimulatory activity of recombinant Mycobacterium bovis BCG that secretes major membrane protein II of Mycobacterium leprae.Infect Immun. 2006 Nov;74(11):6264-71. doi: 10.1128/IAI.00878-06.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] 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.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.