Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4GJX9R)

• DOT Name: ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3)
• Synonyms: EC 3.2.1.113; Alpha-1,2-mannosidase EDEM3
• Gene Name: EDEM3
• Related Disease:
  Congenital disorder of glycosylation, type 2v
  Hepatitis C virus infection
  Prostate carcinoma
• UniProt ID: EDEM3_HUMAN
• EC Number: 3.2.1.113
• Pfam ID: PF01532 ; PF02225
• Sequence:
  MSEAGGRGCGSPVPQRARWRLVAATAAFCLVSATSVWTAGAEPMSREEKQKLGNQVLEMF
  DHAYGNYMEHAYPADELMPLTCRGRVRGQEPSRGDVDDALGKFSLTLIDSLDTLVVLNKT
  KEFEDAVRKVLRDVNLDNDVVVSVFETNIRVLGGLLGGHSLAIMLKEKGEYMQWYNDELL
  QMAKQLGYKLLPAFNTTSGLPYPRINLKFGIRKPEARTGTETDTCTACAGTLILEFAALS
  RFTGATIFEEYARKALDFLWEKRQRSSNLVGVTINIHTGDWVRKDSGVGAGIDSYYEYLL
  KAYVLLGDDSFLERFNTHYDAIMRYISQPPLLLDVHIHKPMLNARTWMDALLAFFPGLQV
  LKGDIRPAIETHEMLYQVIKKHNFLPEAFTTDFRVHWAQHPLRPEFAESTYFLYKATGDP
  YYLEVGKTLIENLNKYARVPCGFAAMKDVRTGSHEDRMDSFFLAEMFKYLYLLFADKEDI
  IFDIEDYIFTTEAHLLPLWLSTTNQSISKKNTTSEYTELDDSNFDWTCPNTQILFPNDPL
  YAQSIREPLKNVVDKSCPRGIIRVEESFRSGAKPPLRARDFMATNPEHLEILKKMGVSLI
  HLKDGRVQLVQHAIQAASSIDAEDGLRFMQEMIELSSQQQKEQQLPPRAVQIVSHPFFGR
  VVLTAGPAQFGLDLSKHKETRGFVASSKPSNGCSELTNPEAVMGKIALIQRGQCMFAEKA
  RNIQNAGAIGGIVIDDNEGSSSDTAPLFQMAGDGKDTDDIKIPMLFLFSKEGSIILDAIR
  EYEEVEVLLSDKAKDRDPEMENEEQPSSENDSQNQSGEQISSSSQEVDLVDQESSEENSL
  NSHPESLSLADMDNAASISPSEQTSNPTENHETTNLNGECTDLDNQLQEQSETEEDSNPN
  VSWGKKVQPIDSILADWNEDIEAFEMMEKDEL
• Function: Involved in endoplasmic reticulum-associated degradation (ERAD). Accelerates the glycoprotein ERAD by proteasomes, by catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 in the N-glycans. May also participate in mannose trimming from all glycoproteins and not just misfolded ones targeted to ERAD. May have alpha 1,2-mannosidase activity.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: ER Quality Control Compartment (ERQC) (R-HSA-901032)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital disorder of glycosylation, type 2v	DISJLJXQ	Strong	Autosomal recessive	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[3]

14 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 3 (EDEM3).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[10]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[15]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of ER degradation-enhancing alpha-mannosidase-like protein 3 (EDEM3).	[16]

References

• [1] Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation. Am J Hum Genet. 2021 Jul 1;108(7):1342-1349. doi: 10.1016/j.ajhg.2021.05.010. Epub 2021 Jun 17.
• [2] Role of the endoplasmic reticulum-associated degradation (ERAD) pathway in degradation of hepatitis C virus envelope proteins and production of virus particles.J Biol Chem. 2011 Oct 28;286(43):37264-73. doi: 10.1074/jbc.M111.259085. Epub 2011 Aug 30.
• [3] Glycosylation is an Androgen-Regulated Process Essential for Prostate Cancer Cell Viability.EBioMedicine. 2016 Jun;8:103-116. doi: 10.1016/j.ebiom.2016.04.018. Epub 2016 Apr 20.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [9] 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.
• [10] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.