Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ASQSE)

• DOT Name: Probable ubiquitin carboxyl-terminal hydrolase FAF-X
• Synonyms: EC 3.4.19.12; Deubiquitinating enzyme FAF-X; Fat facets in mammals; hFAM; Fat facets protein-related, X-linked; Ubiquitin thioesterase FAF-X; Ubiquitin-specific protease 9, X chromosome; Ubiquitin-specific-processing protease FAF-X
• Gene Name: USP9X
• Related Disease:
  Intellectual disability, X-linked 99
  X-linked syndromic intellectual disability
  Intellectual disability, X-linked 99, syndromic, female-restricted
  Non-syndromic X-linked intellectual disability
  X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability
• UniProt ID: USP9X_HUMAN
• PDB ID: 5VBD; 5WCH; 7YXX; 7YXY
• EC Number: 3.4.19.12
• Pfam ID: PF12030 ; PF00443
• Sequence:
  MTATTRGSPVGGNDNQGQAPDGQSQPPLQQNQTSSPDSSNENSPATPPDEQGQGDAPPQL
  EDEEPAFPHTDLAKLDDMINRPRWVVPVLPKGELEVLLEAAIDLSKKGLDVKSEACQRFF
  RDGLTISFTKILTDEAVSGWKFEIHRCIINNTHRLVELCVAKLSQDWFPLLELLAMALNP
  HCKFHIYNGTRPCESVSSSVQLPEDELFARSPDPRSPKGWLVDLLNKFGTLNGFQILHDR
  FINGSALNVQIIAALIKPFGQCYEFLTLHTVKKYFLPIIEMVPQFLENLTDEELKKEAKN
  EAKNDALSMIIKSLKNLASRVPGQEETVKNLEIFRLKMILRLLQISSFNGKMNALNEVNK
  VISSVSYYTHRHGNPEEEEWLTAERMAEWIQQNNILSIVLRDSLHQPQYVEKLEKILRFV
  IKEKALTLQDLDNIWAAQAGKHEAIVKNVHDLLAKLAWDFSPEQLDHLFDCFKASWTNAS
  KKQREKLLELIRRLAEDDKDGVMAHKVLNLLWNLAHSDDVPVDIMDLALSAHIKILDYSC
  SQDRDTQKIQWIDRFIEELRTNDKWVIPALKQIREICSLFGEAPQNLSQTQRSPHVFYRH
  DLINQLQHNHALVTLVAENLATYMESMRLYARDHEDYDPQTVRLGSRYSHVQEVQERLNF
  LRFLLKDGQLWLCAPQAKQIWKCLAENAVYLCDREACFKWYSKLMGDEPDLDPDINKDFF
  ESNVLQLDPSLLTENGMKCFERFFKAVNCREGKLVAKRRAYMMDDLELIGLDYLWRVVIQ
  SNDDIASRAIDLLKEIYTNLGPRLQVNQVVIHEDFIQSCFDRLKASYDTLCVLDGDKDSV
  NCARQEAVRMVRVLTVLREYINECDSDYHEERTILPMSRAFRGKHLSFVVRFPNQGRQVD
  DLEVWSHTNDTIGSVRRCILNRIKANVAHTKIELFVGGELIDPADDRKLIGQLNLKDKSL
  ITAKLTQISSNMPSSPDSSSDSSTGSPGNHGNHYSDGPNPEVESCLPGVIMSLHPRYISF
  LWQVADLGSSLNMPPLRDGARVLMKLMPPDSTTIEKLRAICLDHAKLGESSLSPSLDSLF
  FGPSASQVLYLTEVVYALLMPAGAPLADDSSDFQFHFLKSGGLPLVLSMLTRNNFLPNAD
  METRRGAYLNALKIAKLLLTAIGYGHVRAVAEACQPGVEGVNPMTQINQVTHDQAVVLQS
  ALQSIPNPSSECMLRNVSVRLAQQISDEASRYMPDICVIRAIQKIIWASGCGSLQLVFSP
  NEEITKIYEKTNAGNEPDLEDEQVCCEALEVMTLCFALIPTALDALSKEKAWQTFIIDLL
  LHCHSKTVRQVAQEQFFLMCTRCCMGHRPLLFFITLLFTVLGSTARERAKHSGDYFTLLR
  HLLNYAYNSNINVPNAEVLLNNEIDWLKRIRDDVKRTGETGIEETILEGHLGVTKELLAF
  QTSEKKFHIGCEKGGANLIKELIDDFIFPASNVYLQYMRNGELPAEQAIPVCGSPPTINA
  GFELLVALAVGCVRNLKQIVDSLTEMYYIGTAITTCEALTEWEYLPPVGPRPPKGFVGLK
  NAGATCYMNSVIQQLYMIPSIRNGILAIEGTGSDVDDDMSGDEKQDNESNVDPRDDVFGY
  PQQFEDKPALSKTEDRKEYNIGVLRHLQVIFGHLAASRLQYYVPRGFWKQFRLWGEPVNL
  REQHDALEFFNSLVDSLDEALKALGHPAMLSKVLGGSFADQKICQGCPHRYECEESFTTL
  NVDIRNHQNLLDSLEQYVKGDLLEGANAYHCEKCNKKVDTVKRLLIKKLPPVLAIQLKRF
  DYDWERECAIKFNDYFEFPRELDMEPYTVAGVAKLEGDNVNPESQLIQQSEQSESETAGS
  TKYRLVGVLVHSGQASGGHYYSYIIQRNGGDGERNRWYKFDDGDVTECKMDDDEEMKNQC
  FGGEYMGEVFDHMMKRMSYRRQKRWWNAYILFYERMDTIDQDDELIRYISELAITTRPHQ
  IIMPSAIERSVRKQNVQFMHNRMQYSMEYFQFMKKLLTCNGVYLNPPPGQDHLLPEAEEI
  TMISIQLAARFLFTTGFHTKKVVRGSASDWYDALCILLRHSKNVRFWFAHNVLFNVSNRF
  SEYLLECPSAEVRGAFAKLIVFIAHFSLQDGPCPSPFASPGPSSQAYDNLSLSDHLLRAV
  LNLLRREVSEHGRHLQQYFNLFVMYANLGVAEKTQLLKLSVPATFMLVSLDEGPGPPIKY
  QYAELGKLYSVVSQLIRCCNVSSRMQSSINGNPPLPNPFGDPNLSQPIMPIQQNVADILF
  VRTSYVKKIIEDCSNSEETVKLLRFCCWENPQFSSTVLSELLWQVAYSYTYELRPYLDLL
  LQILLIEDSWQTHRIHNALKGIPDDRDGLFDTIQRSKNHYQKRAYQCIKCMVALFSNCPV
  AYQILQGNGDLKRKWTWAVEWLGDELERRPYTGNPQYTYNNWSPPVQSNETSNGYFLERS
  HSARMTLAKACELCPEEEPDDQDAPDEHESPPPEDAPLYPHSPGSQYQQNNHVHGQPYTG
  PAAHHMNNPQRTGQRAQENYEGSEEVSPPQTKDQ
• Function: Deubiquitinase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. May therefore play an important regulatory role at the level of protein turnover by preventing degradation of proteins through the removal of conjugated ubiquitin. Specifically hydrolyzes 'Lys-63'-, 'Lys-48'-, 'Lys-29'- and 'Lys-33'-linked polyubiquitins chains. Essential component of TGF-beta/BMP signaling cascade. Specifically deubiquitinates monoubiquitinated SMAD4, opposing the activity of E3 ubiquitin-protein ligase TRIM33. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions. Deubiquitinates mTORC2 complex component RICTOR at 'Lys-294' by removing 'Lys-63'-linked polyubiquitin chains, stabilizing RICTOR and enhancing its binding to MTOR, thus promoting mTORC2 complex assembly. Regulates chromosome alignment and segregation in mitosis by regulating the localization of BIRC5/survivin to mitotic centromeres. Involved in axonal growth and neuronal cell migration. Regulates cellular clock function by enhancing the protein stability and transcriptional activity of the core circadian protein BMAL1 via its deubiquitinating activity. Acts as a regulator of peroxisome import by mediating deubiquitination of PEX5: specifically deubiquitinates PEX5 monoubiquitinated at 'Cys-11' following its retrotranslocation into the cytosol, resetting PEX5 for a subsequent import cycle. Deubiquitinates PEG10.
• Tissue Specificity: Widely expressed in embryonic and adult tissues.
• Reactome Pathway:
  Ub-specific processing proteases (R-HSA-5689880)
  Synthesis of active ubiquitin (R-HSA-8866652)
  RHOU GTPase cycle (R-HSA-9013420)
  RHOV GTPase cycle (R-HSA-9013424)
  Peroxisomal protein import (R-HSA-9033241)
  Amyloid fiber formation (R-HSA-977225)
  Downregulation of SMAD2/3 (R-HSA-2173795)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, X-linked 99	DISW92UF	Definitive	X-linked	[1]
X-linked syndromic intellectual disability	DISG1YOH	Definitive	X-linked	[2]
Intellectual disability, X-linked 99, syndromic, female-restricted	DISPG2N1	Strong	X-linked	[3]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[1]
X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability	DISQ8UVL	Supportive	X-linked	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Probable ubiquitin carboxyl-terminal hydrolase FAF-X affects the response to substance of Fluorouracil.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Probable ubiquitin carboxyl-terminal hydrolase FAF-X.	[19]

References

• [1] Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth. Am J Hum Genet. 2014 Mar 6;94(3):470-8. doi: 10.1016/j.ajhg.2014.02.004.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations. Am J Hum Genet. 2016 Feb 4;98(2):373-81. doi: 10.1016/j.ajhg.2015.12.015. Epub 2016 Jan 28.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [11] 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.
• [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] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] 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.
• [16] 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.
• [17] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.