Details of Drug Off-Target (DOT)

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

• DOT Name: Ubiquitin-like modifier-activating enzyme 6
• Synonyms: Ubiquitin-activating enzyme 6; EC 6.2.1.45; Monocyte protein 4; MOP-4; Ubiquitin-activating enzyme E1-like protein 2; E1-L2
• Gene Name: UBA6
• Related Disease: Intellectual disability
• UniProt ID: UBA6_HUMAN
• PDB ID: 7PVN; 7PYV; 7SOL
• EC Number: 6.2.1.45
• Pfam ID: PF16191 ; PF16190 ; PF09358 ; PF00899 ; PF10585
• Sequence:
  MEGSEPVAAHQGEEASCSSWGTGSTNKNLPIMSTASVEIDDALYSRQRYVLGDTAMQKMA
  KSHVFLSGMGGLGLEIAKNLVLAGIKAVTIHDTEKCQAWDLGTNFFLSEDDVVNKRNRAE
  AVLKHIAELNPYVHVTSSSVPFNETTDLSFLDKYQCVVLTEMKLPLQKKINDFCRSQCPP
  IKFISADVHGIWSRLFCDFGDEFEVLDTTGEEPKEIFISNITQANPGIVTCLENHPHKLE
  TGQFLTFREINGMTGLNGSIQQITVISPFSFSIGDTTELEPYLHGGIAVQVKTPKTVFFE
  SLERQLKHPKCLIVDFSNPEAPLEIHTAMLALDQFQEKYSRKPNVGCQQDSEELLKLATS
  ISETLEEKPDVNADIVHWLSWTAQGFLSPLAAAVGGVASQEVLKAVTGKFSPLCQWLYLE
  AADIVESLGKPECEEFLPRGDRYDALRACIGDTLCQKLQNLNIFLVGCGAIGCEMLKNFA
  LLGVGTSKEKGMITVTDPDLIEKSNLNRQFLFRPHHIQKPKSYTAADATLKINSQIKIDA
  HLNKVCPTTETIYNDEFYTKQDVIITALDNVEARRYVDSRCLANLRPLLDSGTMGTKGHT
  EVIVPHLTESYNSHRDPPEEEIPFCTLKSFPAAIEHTIQWARDKFESSFSHKPSLFNKFW
  QTYSSAEEVLQKIQSGHSLEGCFQVIKLLSRRPRNWSQCVELARLKFEKYFNHKALQLLH
  CFPLDIRLKDGSLFWQSPKRPPSPIKFDLNEPLHLSFLQNAAKLYATVYCIPFAEEDLSA
  DALLNILSEVKIQEFKPSNKVVQTDETARKPDHVPISSEDERNAIFQLEKAILSNEATKS
  DLQMAVLSFEKDDDHNGHIDFITAASNLRAKMYSIEPADRFKTKRIAGKIIPAIATTTAT
  VSGLVALEMIKVTGGYPFEAYKNCFLNLAIPIVVFTETTEVRKTKIRNGISFTIWDRWTV
  HGKEDFTLLDFINAVKEKYGIEPTMVVQGVKMLYVPVMPGHAKRLKLTMHKLVKPTTEKK
  YVDLTVSFAPDIDGDEDLPGPPVRYYFSHDTD
• Function: Activates ubiquitin by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a ubiquitin-E1 thioester and free AMP. Specific for ubiquitin, does not activate ubiquitin-like peptides. Differs from UBE1 in its specificity for substrate E2 charging. Does not charge cell cycle E2s, such as CDC34. Essential for embryonic development. Required for UBD/FAT10 conjugation. Isoform 2 may play a key role in ubiquitin system and may influence spermatogenesis and male fertility.
• Tissue Specificity: Widely expressed. Isoform 2 is predominantly expressed in testis with higher expression in adult testis than in fetal testis.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Synthesis of active ubiquitin (R-HSA-8866652)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ubiquitin-like modifier-activating enzyme 6.	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ubiquitin-like modifier-activating enzyme 6.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[10]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Ubiquitin-like modifier-activating enzyme 6.	[13]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Ubiquitin-like modifier-activating enzyme 6.	[14]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Ubiquitin-like modifier-activating enzyme 6.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ubiquitin-like modifier-activating enzyme 6.	[12]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] 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.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [12] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [14] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [15] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.