Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSF03K2)

• DOT Name: Gem-associated protein 5 (GEMIN5)
• Synonyms: Gemin5
• Gene Name: GEMIN5
• Related Disease:
  Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction
  Neoplasm
  Obesity
• UniProt ID: GEMI5_HUMAN
• PDB ID: 5GXH; 5GXI; 5H1J; 5H1K; 5H1L; 5H1M; 5H3S; 5H3T; 5H3U; 5TEE; 5TEF; 5THA; 6RNQ; 6RNS; 7XDT; 7XGR
• Pfam ID: PF12894 ; PF21720 ; PF00400
• Sequence:
  MGQEPRTLPPSPNWYCARCSDAVPGGLFGFAARTSVFLVRVGPGAGESPGTPPFRVIGEL
  VGHTERVSGFTFSHHPGQYNLCATSSDDGTVKIWDVETKTVVTEHALHQHTISTLHWSPR
  VKDLIVSGDEKGVVFCYWFNRNDSQHLFIEPRTIFCLTCSPHHEDLVAIGYKDGIVVIID
  ISKKGEVIHRLRGHDDEIHSIAWCPLPGEDCLSINQEETSEEAEITNGNAVAQAPVTKGC
  YLATGSKDQTIRIWSCSRGRGVMILKLPFLKRRGGGIDPTVKERLWLTLHWPSNQPTQLV
  SSCFGGELLQWDLTQSWRRKYTLFSASSEGQNHSRIVFNLCPLQTEDDKQLLLSTSMDRD
  VKCWDIATLECSWTLPSLGGFAYSLAFSSVDIGSLAIGVGDGMIRVWNTLSIKNNYDVKN
  FWQGVKSKVTALCWHPTKEGCLAFGTDDGKVGLYDTYSNKPPQISSTYHKKTVYTLAWGP
  PVPPMSLGGEGDRPSLALYSCGGEGIVLQHNPWKLSGEAFDINKLIRDTNSIKYKLPVHT
  EISWKADGKIMALGNEDGSIEIFQIPNLKLICTIQQHHKLVNTISWHHEHGSQPELSYLM
  ASGSNNAVIYVHNLKTVIESSPESPVTITEPYRTLSGHTAKITSVAWSPHHDGRLVSASY
  DGTAQVWDALREEPLCNFRGHRGRLLCVAWSPLDPDCIYSGADDFCVHKWLTSMQDHSRP
  PQGKKSIELEKKRLSQPKAKPKKKKKPTLRTPVKLESIDGNEEESMKENSGPVENGVSDQ
  EGEEQAREPELPCGLAPAVSREPVICTPVSSGFEKSKVTINNKVILLKKEPPKEKPETLI
  KKRKARSLLPLSTSLDHRSKEELHQDCLVLATAKHSRELNEDVSADVEERFHLGLFTDRA
  TLYRMIDIEGKGHLENGHPELFHQLMLWKGDLKGVLQTAAERGELTDNLVAMAPAAGYHV
  WLWAVEAFAKQLCFQDQYVKAASHLLSIHKVYEAVELLKSNHFYREAIAIAKARLRPEDP
  VLKDLYLSWGTVLERDGHYAVAAKCYLGATCAYDAAKVLAKKGDAASLRTAAELAAIVGE
  DELSASLALRCAQELLLANNWVGAQEALQLHESLQGQRLVFCLLELLSRHLEEKQLSEGK
  SSSSYHTWNTGTEGPFVERVTAVWKSIFSLDTPEQYQEAFQKLQNIKYPSATNNTPAKQL
  LLHICHDLTLAVLSQQMASWDEAVQALLRAVVRSYDSGSFTIMQEVYSAFLPDGCDHLRD
  KLGDHQSPATPAFKSLEAFFLYGRLYEFWWSLSRPCPNSSVWVRAGHRTLSVEPSQQLDT
  ASTEETDPETSQPEPNRPSELDLRLTEEGERMLSTFKELFSEKHASLQNSQRTVAEVQET
  LAEMIRQHQKSQLCKSTANGPDKNEPEVEAEQPLCSSQSQCKEEKNEPLSLPELTKRLTE
  ANQRMAKFPESIKAWPFPDVLECCLVLLLIRSHFPGCLAQEMQQQAQELLQKYGNTKTYR
  RHCQTFCM
• Function: The SMN complex catalyzes the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome, and thereby plays an important role in the splicing of cellular pre-mRNAs. Most spliceosomal snRNPs contain a common set of Sm proteins SNRPB, SNRPD1, SNRPD2, SNRPD3, SNRPE, SNRPF and SNRPG that assemble in a heptameric protein ring on the Sm site of the small nuclear RNA to form the core snRNP (Sm core). In the cytosol, the Sm proteins SNRPD1, SNRPD2, SNRPE, SNRPF and SNRPG are trapped in an inactive 6S pICln-Sm complex by the chaperone CLNS1A that controls the assembly of the core snRNP. To assemble core snRNPs, the SMN complex accepts the trapped 5Sm proteins from CLNS1A forming an intermediate. Binding of snRNA inside 5Sm ultimately triggers eviction of the SMN complex, thereby allowing binding of SNRPD3 and SNRPB to complete assembly of the core snRNP. Within the SMN complex, GEMIN5 recognizes and delivers the small nuclear RNAs (snRNAs) to the SMN complex. Binds to the 7-methylguanosine cap of RNA molecules. Binds to the 3'-UTR of SMN1 mRNA and regulates its translation; does not affect mRNA stability. May play a role in the regulation of protein synthesis via its interaction with ribosomes.
• Reactome Pathway:
  SARS-CoV-2 modulates host translation machinery (R-HSA-9754678)
  snRNP Assembly (R-HSA-191859)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder with cerebellar atrophy and motor dysfunction	DIS7ISB5	Strong	Autosomal recessive	[1]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[2]
Obesity	DIS47Y1K	Limited	Biomarker	[3]

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 Gem-associated protein 5 (GEMIN5).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Gem-associated protein 5 (GEMIN5).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Gem-associated protein 5 (GEMIN5).	[14]

12 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 Gem-associated protein 5 (GEMIN5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gem-associated protein 5 (GEMIN5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Gem-associated protein 5 (GEMIN5).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Gem-associated protein 5 (GEMIN5).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gem-associated protein 5 (GEMIN5).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Gem-associated protein 5 (GEMIN5).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Gem-associated protein 5 (GEMIN5).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Gem-associated protein 5 (GEMIN5).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Gem-associated protein 5 (GEMIN5).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Gem-associated protein 5 (GEMIN5).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Gem-associated protein 5 (GEMIN5).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Gem-associated protein 5 (GEMIN5).	[17]

References

• [1] Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder. Nat Commun. 2021 May 7;12(1):2558. doi: 10.1038/s41467-021-22627-w.
• [2] Alterations in Gemin5 expression contribute to alternative mRNA splicing patterns and tumor cell motility.Cancer Res. 2008 Feb 1;68(3):639-44. doi: 10.1158/0008-5472.CAN-07-2632.
• [3] Regulated expression of Gemin5, Xrn1, Cpeb and Stau1 in the uterus and ovaries after superovulation and the effect of exogenous estradiol and leptin in rodents.Mol Biol Rep. 2019 Apr;46(2):2533-2540. doi: 10.1007/s11033-019-04606-z. Epub 2019 Jan 28.
• [4] 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.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] 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.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.