Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQXYD65)

• DOT Name: ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2)
• Gene Name: EDEM2
• Related Disease:
  Alzheimer disease
  Leiomyoma
  Schizophrenia
  Uterine fibroids
• UniProt ID: EDEM2_HUMAN
• Pfam ID: PF01532
• Sequence:
  MPFRLLIPLGLLCALLPQHHGAPGPDGSAPDPAHYRERVKAMFYHAYDSYLENAFPFDEL
  RPLTCDGHDTWGSFSLTLIDALDTLLILGNVSEFQRVVEVLQDSVDFDIDVNASVFETNI
  RVVGGLLSAHLLSKKAGVEVEAGWPCSGPLLRMAEEAARKLLPAFQTPTGMPYGTVNLLH
  GVNPGETPVTCTAGIGTFIVEFATLSSLTGDPVFEDVARVALMRLWESRSDIGLVGNHID
  VLTGKWVAQDAGIGAGVDSYFEYLVKGAILLQDKKLMAMFLEYNKAIRNYTRFDDWYLWV
  QMYKGTVSMPVFQSLEAYWPGLQSLIGDIDNAMRTFLNYYTVWKQFGGLPEFYNIPQGYT
  VEKREGYPLRPELIESAMYLYRATGDPTLLELGRDAVESIEKISKVECGFATIKDLRDHK
  LDNRMESFFLAETVKYLYLLFDPTNFIHNNGSTFDAVITPYGECILGAGGYIFNTEAHPI
  DPAALHCCQRLKEEQWEVEDLMREFYSLKRSRSKFQKNTVSSGPWEPPARPGTLFSPENH
  DQARERKPAKQKVPLLSCPSQPFTSKLALLGQVFLDSS
• Function: Involved in the endoplasmic reticulum-associated degradation (ERAD) pathway that targets misfolded glycoproteins for degradation in an N-glycan-dependent manner. May initiate ERAD by promoting the first mannose trimming step of ERAD substrates, from Man9GlcNAc2 to Man8GlcNAc2. Seems to recognize and bind to exposed hydrophobic regions in target proteins.
• Tissue Specificity: Expressed ubiquitously in all tissues tested with slightly higher levels detected in small intestine and peripheral blood leukocytes and weakest levels in brain and skeletal muscle.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Maturation of spike protein (R-HSA-9694548)
  ER Quality Control Compartment (ERQC) (R-HSA-901032)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Leiomyoma	DISLDDFN	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[2]

6 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 degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[11]

2 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 decreases the methylation of ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of ER degradation-enhancing alpha-mannosidase-like protein 2 (EDEM2).	[10]

References

• [1] Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis.Am J Med Genet B Neuropsychiatr Genet. 2009 Jan 5;150B(1):50-5. doi: 10.1002/ajmg.b.30767.
• [2] Transethnic and race-stratified genome-wide association study of fibroid characteristics in African American and European American women.Fertil Steril. 2018 Sep;110(4):737-745.e34. doi: 10.1016/j.fertnstert.2018.04.035.
• [3] Exome sequencing supports a de novo mutational paradigm for schizophrenia.Nat Genet. 2011 Aug 7;43(9):864-8. doi: 10.1038/ng.902.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [9] 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.
• [10] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.