Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYAH4LX)

• DOT Name: ER membrane protein complex subunit 1 (EMC1)
• Gene Name: EMC1
• Related Disease:
  Cerebellar atrophy, visual impairment, and psychomotor retardation
  Congenital anomaly of kidney and urinary tract
  Epilepsy
  Movement disorder
  Complex neurodevelopmental disorder with motor features
  Intellectual disability
  Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome
• UniProt ID: EMC1_HUMAN
• PDB ID: 6WW7; 6Z3W; 7ADO; 7ADP; 8EOI; 8S9S
• Pfam ID: PF07774 ; PF13360
• Sequence:
  MAAEWASRFWLWATLLIPAAAVYEDQVGKFDWRQQYVGKVKFASLEFSPGSKKLVVATEK
  NVIAALNSRTGEILWRHVDKGTAEGAVDAMLLHGQDVITVSNGGRIMRSWETNIGGLNWE
  ITLDSGSFQALGLVGLQESVRYIAVLKKTTLALHHLSSGHLKWVEHLPESDSIHYQMVYS
  YGSGVVWALGVVPFSHVNIVKFNVEDGEIVQQVRVSTPWLQHLSGACGVVDEAVLVCPDP
  SSRSLQTLALETEWELRQIPLQSLDLEFGSGFQPRVLPTQPNPVDASRAQFFLHLSPSHY
  ALLQYHYGTLSLLKNFPQTALVSFATTGEKTVAAVMACRNEVQKSSSSEDGSMGSFSEKS
  SSKDSLACFNQTYTINLYLVETGRRLLDTTITFSLEQSGTRPERLYIQVFLKKDDSVGYR
  ALVQTEDHLLLFLQQLAGKVVLWSREESLAEVVCLEMVDLPLTGAQAELEGEFGKKADGL
  LGMFLKRLSSQLILLQAWTSHLWKMFYDARKPRSQIKNEINIDTLARDEFNLQKMMVMVT
  ASGKLFGIESSSGTILWKQYLPNVKPDSSFKLMVQRTTAHFPHPPQCTLLVKDKESGMSS
  LYVFNPIFGKWSQVAPPVLKRPILQSLLLPVMDQDYAKVLLLIDDEYKVTAFPATRNVLR
  QLHELAPSIFFYLVDAEQGRLCGYRLRKDLTTELSWELTIPPEVQRIVKVKGKRSSEHVH
  SQGRVMGDRSVLYKSLNPNLLAVVTESTDAHHERTFIGIFLIDGVTGRIIHSSVQKKAKG
  PVHIVHSENWVVYQYWNTKARRNEFTVLELYEGTEQYNATAFSSLDRPQLPQVLQQSYIF
  PSSISAMEATITERGITSRHLLIGLPSGAILSLPKALLDPRRPEIPTEQSREENLIPYSP
  DVQIHAERFINYNQTVSRMRGIYTAPSGLESTCLVVAYGLDIYQTRVYPSKQFDVLKDDY
  DYVLISSVLFGLVFATMITKRLAQVKLLNRAWR
• 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).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar atrophy, visual impairment, and psychomotor retardation;	DIS03X0H	Strong	Autosomal recessive	[1]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Strong	Genetic Variation	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[4]
Complex neurodevelopmental disorder with motor features	DIS09FBL	Moderate	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[4]
Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome	DISLW2CX	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ER membrane protein complex subunit 1 (EMC1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of ER membrane protein complex subunit 1 (EMC1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of ER membrane protein complex subunit 1 (EMC1).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of ER membrane protein complex subunit 1 (EMC1).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of ER membrane protein complex subunit 1 (EMC1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ER membrane protein complex subunit 1 (EMC1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ER membrane protein complex subunit 1 (EMC1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ER membrane protein complex subunit 1 (EMC1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ER membrane protein complex subunit 1 (EMC1).	[12]

References

• [1] Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013 Feb;23(2):236-47. doi: 10.1101/gr.144105.112. Epub 2012 Oct 26.
• [2] Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.Genet Med. 2017 Apr;19(4):412-420. doi: 10.1038/gim.2016.131. Epub 2016 Sep 22.
• [3] A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy. Mol Genet Genomic Med. 2018 Mar;6(2):282-287. doi: 10.1002/mgg3.352. Epub 2017 Dec 22.
• [4] Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. Am J Hum Genet. 2016 Mar 3;98(3):562-570. doi: 10.1016/j.ajhg.2016.01.011.
• [5] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [6] 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.
• [7] 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.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] 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.
• [14] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.