Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT73FVYZ)

• DOT Name: Probable E3 ubiquitin-protein ligase HERC1 (HERC1)
• Synonyms: EC 2.3.2.26; HECT domain and RCC1-like domain-containing protein 1; HECT-type E3 ubiquitin transferase HERC1; p532; p619
• Gene Name: HERC1
• Related Disease:
  Macrocephaly, dysmorphic facies, and psychomotor retardation
  T lymphoblastic leukaemia
  Age-related macular degeneration
  Angelman syndrome
  Atrial fibrillation
  Autism spectrum disorder
  Intellectual disability
  Familial atrial fibrillation
  Megalencephaly-severe kyphoscoliosis-overgrowth syndrome
  Chronic obstructive pulmonary disease
  Megalencephaly
• UniProt ID: HERC1_HUMAN
• PDB ID: 4O2W; 4QT6
• EC Number: 2.3.2.26
• Pfam ID: PF00632 ; PF00415 ; PF00622 ; PF00400
• Sequence:
  MATMIPPVKLKWLEHLNSSWITEDSESIATREGVAVLYSKLVSNKEVVPLPQQVLCLKGP
  QLPDFERESLSSDEQDHYLDALLSSQLALAKMVCSDSPFAGALRKRLLVLQRVFYALSNK
  YHDKGKVKQQQHSPESSSGSADVHSVSERPRSSTDALIEMGVRTGLSLLFALLRQSWMMP
  VSGPGLSLCNDVIHTAIEVVSSLPPLSLANESKIPPMGLDCLSQVTTFLKGVTIPNSGAD
  TLGRRLASELLLGLAAQRGSLRYLLEWIEMALGASAVVHTMEKGKLLSSQEGMISFDCFM
  TILMQMRRSLGSSADRSQWREPTRTSDGLCSLYEAALCLFEEVCRMASDYSRTCASPDSI
  QTGDAPIVSETCEVYVWGSNSSHQLVEGTQEKILQPKLAPSFSDAQTIEAGQYCTFVIST
  DGSVRACGKGSYGRLGLGDSNNQSTLKKLTFEPHRSIKKVSSSKGSDGHTLAFTTEGEVF
  SWGDGDYGKLGHGNSSTQKYPKLIQGPLQGKVVVCVSAGYRHSAAVTEDGELYTWGEGDF
  GRLGHGDSNSRNIPTLVKDISNVGEVSCGSSHTIALSKDGRTVWSFGGGDNGKLGHGDTN
  RVYKPKVIEALQGMFIRKVCAGSQSSLALTSTGQVYAWGCGACLGCGSSEATALRPKLIE
  ELAATRIVDVSIGDSHCLALSHDNEVYAWGNNSMGQCGQGNSTGPITKPKKVSGLDGIAI
  QQISAGTSHSLAWTALPRDRQVVAWHRPYCVDLEESTFSHLRSFLERYCDKINSEIPPLP
  FPSSREHHSFLKLCLKLLSNHLALALAGGVATSILGRQAGPLRNLLFRLMDSTVPDEIQE
  VVIETLSVGATMLLPPLRERMELLHSLLPQGPDRWESLSKGQRMQLDIILTSLQDHTHVA
  SLLGYSSPSDAADLSSVCTGYGNLSDQPYGTQSCHPDTHLAEILMKTLLRNLGFYTDQAF
  GELEKNSDKFLLGTSSSENSQPAHLHELLCSLQKQLLAFCHINNISENSSSVALLHKHLQ
  LLLPHATDIYSRSANLLKESPWNGSVGEKLRDVIYVSAAGSMLCQIVNSLLLLPVSVARP
  LLSYLLDLLPPLDCLNRLLPAADLLEDQELQWPLHGGPELIDPAGLPLPQPAQSWVWLVD
  LERTIALLIGRCLGGMLQGSPVSPEEQDTAYWMKTPLFSDGVEMDTPQLDKCMSCLLEVA
  LSGNEEQKPFDYKLRPEIAVYVDLALGCSKEPARSLWISMQDYAVSKDWDSATLSNESLL
  DTVSRFVLAALLKHTNLLSQACGESRYQPGKHLSEVYRCVYKVRSRLLACKNLELIQTRS
  SSRDRWISENQDSADVDPQEHSFTRTIDEEAEMEEQAERDREEGHPEPEDEEEEREHEVM
  TAGKIFQCFLSAREVARSRDRDRMNSGAGSGARADDPPPQSQQERRVSTDLPEGQDVYTA
  ACNSVIHRCALLILGVSPVIDELQKRREEGQLQQPSTSASEGGGLMTRSESLTAESRLVH
  TSPNYRLIKSRSESDLSQPESDEEGYALSGRRNVDLDLAASHRKRGPMHSQLESLSDSWA
  RLKHSRDWLCNSSYSFESDFDLTKSLGVHTLIENVVSFVSGDVGNAPGFKEPEESMSTSP
  QASIIAMEQQQLRAELRLEALHQILVLLSGMEEKGSISLAGSRLSSGFQSSTLLTSVRLQ
  FLAGCFGLGTVGHTGGKGESGRLHHYQDGIRAAKRNIQIEIQVAVHKIYQQLSATLERAL
  QANKHHIEAQQRLLLVTVFALSVHYQPVDVSLAISTGLLNVLSQLCGTDTMLGQPLQLLP
  KTGVSQLSTALKVASTRLLQILAITTGTYADKLSPKVVQSLLDLLCSQLKNLLSQTGVLH
  MASFGEGEQEDGEEEEKKVDSSGETEKKDFRAALRKQHAAELHLGDFLVFLRRVVSSKAI
  QSKMASPKWTEVLLNIASQKCSSGIPLVGNLRTRLLALHVLEAVLPACESGVEDDQMAQI
  VERLFSLLSDCMWETPIAQAKHAIQIKEKEQEIKLQKQGELEEEDENLPIQEVSFDPEKA
  QCCLVENGQILTHGSGGKGYGLASTGVTSGCYQWKFYIVKENRGNEGTCVGVSRWPVHDF
  NHRTTSDMWLYRAYSGNLYHNGEQTLTLSSFTQGDFITCVLDMEARTISFGKNGEEPKLA
  FEDVDAAELYPCVMFYSSNPGEKVKICDMQMRGTPRDLLPGDPICSPVAAVLAEATIQLI
  RILHRTDRWTYCINKKMMERLHKIKICIKESGQKLKKSRSVQSREENEMREEKESKEEEK
  GKHTRHGLADLSELQLRTLCIEVWPVLAVIGGVDAGLRVGGRCVHKQTGRHATLLGVVKE
  GSTSAKVQWDEAEITISFPTFWSPSDTPLYNLEPCEPLPFDVARFRGLTASVLLDLTYLT
  GVHEDMGKQSTKRHEKKHRHESEEKGDVEQKPESESALDMRTGLTSDDVKSQSTTSSKSE
  NEIASFSLDPTLPSVESQHQITEGKRKNHEHMSKNHDVAQSEIRAVQLSYLYLGAMKSLS
  ALLGCSKYAELLLIPKVLAENGHNSDCASSPVVHEDVEMRAALQFLMRHMVKRAVMRSPI
  KRALGLADLERAQAMIYKLVVHGLLEDQFGGKIKQEIDQQAEESDPAQQAQTPVTTSPSA
  SSTTSFMSSSLEDTTTATTPVTDTETVPASESPGVMPLSLLRQMFSSYPTTTVLPTRRAQ
  TPPISSLPTSPSDEVGRRQSLTSPDSQSARPANRTALSDPSSRLSTSPPPPAIAVPLLEM
  GFSLRQIAKAMEATGARGEADAQNITVLAMWMIEHPGHEDEEEPQSGSTADSRPGAAVLG
  SGGKSNDPCYLQSPGDIPSADAAEMEEGFSESPDNLDHTENAASGSGPSARGRSAVTRRH
  KFDLAARTLLARAAGLYRSVQAHRNQSRREGISLQQDPGALYDFNLDEELEIDLDDEAME
  AMFGQDLTSDNDILGMWIPEVLDWPTWHVCESEDREEVVVCELCECSVVSFNQHMKRNHP
  GCGRSANRQGYRSNGSYVDGWFGGECGSGNPYYLLCGTCREKYLAMKTKSKSTSSERYKG
  QAPDLIGKQDSVYEEDWDMLDVDEDEKLTGEEEFELLAGPLGLNDRRIVPEPVQFPDSDP
  LGASVAMVTATNSMEETLMQIGCHGSVEKSSSGRITLGEQAAALANPHDRVVALRRVTAA
  AQVLLARTMVMRALSLLSVSGSSCSLAAGLESLGLTDIRTLVRLMCLAAAGRAGLSTSPS
  AMASTSERSRGGHSKANKPISCLAYLSTAVGCLASNAPSAAKLLVQLCTQNLISAATGVN
  LTTVDDSIQRKFLPSFLRGIAEENKLVTSPNFVVTQALVALLADKGAKLRPNYDKSEVEK
  KGPLELANALAACCLSSRLSSQHRQWAAQQLVRTLAAHDRDNQTTLQTLADMGGDLRKCS
  FIKLEAHQNRVMTCVWCNKKGLLATSGNDGTIRVWNVTKKQYSLQQTCVFNRLEGDAEES
  LGSPSDPSFSPVSWSISGKYLAGALEKMVNIWQVNGGKGLVDIQPHWVSALAWPEEGPAT
  AWSGESPELLLVGRMDGSLGLIEVVDVSTMHRRELEHCYRKDVSVTCIAWFSEDRPFAVG
  YFDGKLLLGTKEPLEKGGIVLIDAHKDTLISMKWDPTGHILMTCAKEDSVKLWGSISGCW
  CCLHSLCHPSIVNGIAWCRLPGKGSKLQLLMATGCQSGLVCVWRIPQDTTQTNVTSAEGW
  WEQESNCQDGYRKSSGAKCVYQLRGHITPVRTVAFSSDGLALVSGGLGGLMNIWSLRDGS
  VLQTVVIGSGAIQTTVWIPEVGVAACSNRSKDVLVVNCTAEWAAANHVLATCRTALKQQG
  VLGLNMAPCMRAFLERLPMMLQEQYAYEKPHVVCGDQLVHSPYMQCLASLAVGLHLDQLL
  CNPPVPPHHQNCLPDPASWNPNEWAWLECFSTTIKAAEALTNGAQFPESFTVPDLEPVPE
  DELVFLMDNSKWINGMDEQIMSWATSRPEDWHLGGKCDVYLWGAGRHGQLAEAGRNVMVP
  AAAPSFSQAQQVICGQNCTFVIQANGTVLACGEGSYGRLGQGNSDDLHVLTVISALQGFV
  VTQLVTSCGSDGHSMALTESGEVFSWGDGDYGKLGHGNSDRQRRPRQIEALQGEEVVQMS
  CGFKHSAVVTSDGKLFTFGNGDYGRLGLGNTSNKKLPERVTALEGYQIGQVACGLNHTLA
  VSADGSMVWAFGDGDYGKLGLGNSTAKSSPQKIDVLCGIGIKKVACGTQFSVALTKDGHV
  YTFGQDRLIGLPEGRARNHNRPQQIPVLAGVIIEDVAVGAEHTLALASNGDVYAWGSNSE
  GQLGLGHTNHVREPTLVTGLQGKNVRQISAGRCHSAAWTAPPVPPRAPGVSVPLQLGLPD
  TVPPQYGALREVSIHTVRARLRLLYHFSDLMYSSWRLLNLSPNNQNSTSHYNAGTWGIVQ
  GQLRPLLAPRVYTLPMVRSIGKTMVQGKNYGPQITVKRISTRGRKCKPIFVQIARQVVKL
  NASDLRLPSRAWKVKLVGEGADDAGGVFDDTITEMCQELETGIVDLLIPSPNATAEVGYN
  RDRFLFNPSACLDEHLMQFKFLGILMGVAIRTKKPLDLHLAPLVWKQLCCVPLTLEDLEE
  VDLLYVQTLNSILHIEDSGITEESFHEMIPLDSFVGQSADGKMVPIIPGGNSIPLTFSNR
  KEYVERAIEYRLHEMDRQVAAVREGMSWIVPVPLLSLLTAKQLEQMVCGMPEISVEVLKK
  VVRYREVDEQHQLVQWFWHTLEEFSNEERVLFMRFVSGRSRLPANTADISQRFQIMKVDR
  PYDSLPTSQTCFFQLRLPPYSSQLVMAERLRYAINNCRSIDMDNYMLSRNVDNAEGSDTD
  Y
• Function: Involved in membrane trafficking via some guanine nucleotide exchange factor (GEF) activity and its ability to bind clathrin. Acts as a GEF for Arf and Rab, by exchanging bound GDP for free GTP. Binds phosphatidylinositol 4,5-bisphosphate, which is required for GEF activity. May also act as a E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Macrocephaly, dysmorphic facies, and psychomotor retardation	DISES5W5	Definitive	Autosomal recessive	[1]
T lymphoblastic leukaemia	DIS2PNPP	Definitive	Genetic Variation	[2]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[3]
Angelman syndrome	DIS4QVXO	Strong	Genetic Variation	[4]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[5]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[7]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[5]
Megalencephaly-severe kyphoscoliosis-overgrowth syndrome	DISCKFB4	Supportive	Autosomal recessive	[1]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[8]
Megalencephaly	DISYW5SV	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[21]

2 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 affects the phosphorylation of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Probable E3 ubiquitin-protein ligase HERC1 (HERC1).	[18]

References

• [1] Biallelic HERC1 mutations in a syndromic form of overgrowth and intellectual disability. Clin Genet. 2015 Oct;88(4):e1-3. doi: 10.1111/cge.12634. Epub 2015 Jul 27.
• [2] SAMHD1 is recurrently mutated in T-cell prolymphocytic leukemia.Blood Cancer J. 2018 Jan 19;8(1):11. doi: 10.1038/s41408-017-0036-5.
• [3] Genome-wide analysis of disease progression in age-related macular degeneration.Hum Mol Genet. 2018 Mar 1;27(5):929-940. doi: 10.1093/hmg/ddy002.
• [4] A homozygous missense mutation in HERC2 associated with global developmental delay and autism spectrum disorder. Hum Mutat. 2012 Dec;33(12):1639-46. doi: 10.1002/humu.22237.
• [5] Biobank-driven genomic discovery yields new insight into atrial fibrillation biology.Nat Genet. 2018 Sep;50(9):1234-1239. doi: 10.1038/s41588-018-0171-3. Epub 2018 Jul 30.
• [6] Whole-exome sequencing and neurite outgrowth analysis in autism spectrum disorder.J Hum Genet. 2016 Mar;61(3):199-206. doi: 10.1038/jhg.2015.141. Epub 2015 Nov 19.
• [7] HERC1 mutations in idiopathic intellectual disability.Eur J Med Genet. 2017 May;60(5):279-283. doi: 10.1016/j.ejmg.2017.03.007. Epub 2017 Mar 18.
• [8] Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis.Respir Res. 2019 Apr 2;20(1):64. doi: 10.1186/s12931-019-1036-8.
• [9] A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy.Eur J Hum Genet. 2016 Mar;24(3):455-8. doi: 10.1038/ejhg.2015.140. Epub 2015 Jul 8.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] 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.
• [13] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [16] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [17] 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.
• [18] 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.
• [19] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.