Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWHN69S)

• DOT Name: ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1)
• Gene Name: EDEM1
• Related Disease:
  Hepatitis C virus infection
  Major depressive disorder
  Obesity
  Post-traumatic stress disorder
  Enterovirus infection
  Melanoma
• UniProt ID: EDEM1_HUMAN
• Pfam ID: PF01532
• Sequence:
  MQWRALVLGLVLLRLGLHGVLWLVFGLGPSMGFYQRFPLSFGFQRLRSPDGPASPTSGPV
  GRPGGVSGPSWLQPPGTGAAQSPRKAPRRPGPGMCGPANWGYVLGGRGRGPDEYEKRYSG
  AFPPQLRAQMRDLARGMFVFGYDNYMAHAFPQDELNPIHCRGRGPDRGDPSNLNINDVLG
  NYSLTLVDALDTLAIMGNSSEFQKAVKLVINTVSFDKDSTVQVFEATIRVLGSLLSAHRI
  ITDSKQPFGDMTIKDYDNELLYMAHDLAVRLLPAFENTKTGIPYPRVNLKTGVPPDTNNE
  TCTAGAGSLLVEFGILSRLLGDSTFEWVARRAVKALWNLRSNDTGLLGNVVNIQTGHWVG
  KQSGLGAGLDSFYEYLLKSYILFGEKEDLEMFNAAYQSIQNYLRRGREACNEGEGDPPLY
  VNVNMFSGQLMNTWIDSLQAFFPGLQVLIGDVEDAICLHAFYYAIWKRYGALPERYNWQL
  QAPDVLFYPLRPELVESTYLLYQATKNPFYLHVGMDILQSLEKYTKVKCGYATLHHVIDK
  STEDRMESFFLSETCKYLYLLFDEDNPVHKSGTRYMFTTEGHIVSVDEHLRELPWKEFFS
  EEGGQDQGGKSVHRPKPHELKVINSSSNCNRVPDERRYSLPLKSIYMRQIDQMVGLI
• Function: Extracts misfolded glycoproteins, but not glycoproteins undergoing productive folding, from the calnexin cycle. It is directly involved in endoplasmic reticulum-associated degradation (ERAD) and targets misfolded glycoproteins for degradation in an N-glycan-independent manner, probably by forming a complex with SEL1L. It has low mannosidase activity, catalyzing mannose trimming from Man8GlcNAc2 to Man7GlcNAc2.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  ER Quality Control Compartment (ERQC) (R-HSA-901032)
  XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[1]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Altered Expression	[3]
Post-traumatic stress disorder	DISHL1EY	Strong	Altered Expression	[2]
Enterovirus infection	DISH2UDP	Limited	Altered Expression	[4]
Melanoma	DIS1RRCY	Limited	Biomarker	[5]

13 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 1 (EDEM1).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[12]
Nilotinib	DM7HXWT	Approved	Nilotinib increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[16]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[17]
L-Serine	DM6WPIS	Investigative	L-Serine increases the expression of ER degradation-enhancing alpha-mannosidase-like protein 1 (EDEM1).	[18]

1 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 1 (EDEM1).	[14]

References

• [1] 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.
• [2] Elevated systemic expression of ER stress related genes is associated with stress-related mental disorders in the Detroit Neighborhood Health Study.Psychoneuroendocrinology. 2014 May;43:62-70. doi: 10.1016/j.psyneuen.2014.01.013. Epub 2014 Feb 7.
• [3] Tissue cell stress response to obesity and its interaction with late gestation diet.Reprod Fertil Dev. 2018 Mar;30(3):430-441. doi: 10.1071/RD16494.
• [4] Inhibition of enterovirus 71 entry by transcription factor XBP1.Biochem Biophys Res Commun. 2012 Apr 20;420(4):882-7. doi: 10.1016/j.bbrc.2012.03.094. Epub 2012 Mar 24.
• [5] Profiling Optimal Conditions for Capturing EDEM Proteins Complexes in Melanoma Using Mass Spectrometry.Adv Exp Med Biol. 2019;1140:155-167. doi: 10.1007/978-3-030-15950-4_9.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Antihypertrophic Effects of Small Molecules that Maintain Mitochondrial ATP Levels Under Hypoxia. EBioMedicine. 2017 Oct;24:147-158. doi: 10.1016/j.ebiom.2017.09.022. Epub 2017 Sep 19.
• [11] Endoplasmic reticulum stress-mediated apoptosis in imatinib-resistant leukemic K562-r cells triggered by AMN107 combined with arsenic trioxide. Exp Biol Med (Maywood). 2013 Aug 1;238(8):932-42. doi: 10.1177/1535370213492689. Epub 2013 Jul 24.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Paraquat activates the IRE1/ASK1/JNK cascade associated with apoptosis in human neuroblastoma SH-SY5Y cells. Toxicol Lett. 2009 Dec 15;191(2-3):203-10. doi: 10.1016/j.toxlet.2009.08.024. Epub 2009 Sep 6.
• [18] Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.