Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSYV9R3)

• DOT Name: Apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1)
• Synonyms: EC 2.3.2.26; Apoptosis-resistant HECT-type E3 ubiquitin transferase 1
• Gene Name: AREL1
• Related Disease:
  Advanced cancer
  Anxiety
  Major depressive disorder
  Mood disorder
  Pneumonia
  Pneumonitis
• UniProt ID: AREL1_HUMAN
• PDB ID: 6JX5; 6LOH
• EC Number: 2.3.2.26
• Pfam ID: PF00630 ; PF00632
• Sequence:
  MFYVIGGITVSVVAFFFTIKFLFELAARVVSFLQNEDRERRGDRTIYDYVRGNYLDPRSC
  KVSWDWKDPYEVGHSMAFRVHLFYKNGQPFPAHRPVGLRVHISHVELAVEIPVTQEVLQE
  PNSNVVKVAFTVRKAGRYEITVKLGGLNVAYSPYYKIFQPGMVVPSKTKIVCHFSTLVLT
  CGQPHTLQIVPRDEYDNPTNNSMSLRDEHNYTLSIHELGPQEEESTGVSFEKSVTSNRQT
  FQVFLRLTLHSRGCFHACISYQNQPINNGEFDIIVLSEDEKNIVERNVSTSGVSIYFEAY
  LYNATNCSSTPWHLPPMHMTSSQRRPSTAVDEEDEDSPSECHTPEKVKKPKKVYCYVSPK
  QFSVKEFYLKIIPWRLYTFRVCPGTKFSYLGPDPVHKLLTLVVDDGIQPPVELSCKERNI
  LAATFIRSLHKNIGGSETFQDKVNFFQRELRQVHMKRPHSKVTLKVSRHALLESSLKATR
  NFSISDWSKNFEVVFQDEEALDWGGPRREWFELICKALFDTTNQLFTRFSDNNQALVHPN
  PNRPAHLRLKMYEFAGRLVGKCLYESSLGGAYKQLVRARFTRSFLAQIIGLRMHYKYFET
  DDPEFYKSKVCFILNNDMSEMELVFAEEKYNKSGQLDKVVELMTGGAQTPVTNANKIFYL
  NLLAQYRLASQVKEEVEHFLKGLNELVPENLLAIFDENELELLMCGTGDISVSDFKAHAV
  VVGGSWHFREKVMRWFWTVVSSLTQEELARLLQFTTGSSQLPPGGFAALCPSFQIIAAPT
  HSTLPTAHTCFNQLCLPTYDSYEEVHRMLQLAISEGCEGFGML
• Function: E3 ubiquitin-protein ligase that catalyzes 'Lys-11'- or 'Lys-33'-linked polyubiquitin chains, with some preference for 'Lys-33' linkages. E3 ubiquitin-protein ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Ubiquitinates SEPTIN4, DIABLO/SMAC and HTRA2 in vitro. Modulates pulmonary inflammation by targeting SOCS2 for ubiquitination and subsequent degradation by the proteasome.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Anxiety	DISIJDBA	Strong	Genetic Variation	[2]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[2]
Pneumonia	DIS8EF3M	Strong	Biomarker	[4]
Pneumonitis	DIS88E0K	Strong	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1).	[6]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1).	[10]

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 affects the methylation of Apoptosis-resistant E3 ubiquitin protein ligase 1 (AREL1).	[8]

References

• [1] Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activities in vitro.J Biol Chem. 2019 Dec 27;294(52):19934-19949. doi: 10.1074/jbc.RA119.010327. Epub 2019 Nov 15.
• [2] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [3] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [4] KIAA0317 regulates pulmonary inflammation through SOCS2 degradation.JCI Insight. 2019 Oct 3;4(19):e129110. doi: 10.1172/jci.insight.129110.
• [5] 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.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [8] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.