Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFPW8DE)

• DOT Name: Origin recognition complex subunit 5 (ORC5)
• Gene Name: ORC5
• Related Disease:
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Myelodysplastic syndrome
  Myeloid leukaemia
  Neoplasm
  Progressive multifocal leukoencephalopathy
  Uterine fibroids
• UniProt ID: ORC5_HUMAN
• PDB ID: 5UJ7; 5UJM; 7CTE; 7CTF; 7CTG; 7JPO; 7JPP; 7JPQ; 7JPR; 7JPS
• Pfam ID: PF13191 ; PF14630 ; PF21639
• Sequence:
  MPHLENVVLCRESQVSILQSLFGERHHFSFPSIFIYGHTASGKTYVTQTLLKTLELPHVF
  VNCVECFTLRLLLEQILNKLNHLSSSEDGCSTEITCETFNDFVRLFKQVTTAENLKDQTV
  YIVLDKAEYLRDMEANLLPGFLRLQELADRNVTVLFLSEIVWEKFRPNTGCFEPFVLYFP
  DYSIGNLQKILSHDHPPEYSADFYAAYINILLGVFYTVCRDLKELRHLAVLNFPKYCEPV
  VKGEASERDTRKLWRNIEPHLKKAMQTVYLREISSSQWEKLQKDDTDPGQLKGLSAHTHV
  ELPYYSKFILIAAYLASYNPARTDKRFFLKHHGKIKKTNFLKKHEKTSNHLLGPKPFPLD
  RLLAILYSIVDSRVAPTANIFSQITSLVTLQLLTLVGHDDQLDGPKYKCTVSLDFIRAIA
  RTVNFDIIKYLYDFL
• Function: Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication.
• Tissue Specificity: Abundant in spleen, ovary, prostate, testis, and colon mucosa.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Activation of ATR in response to replication stress (R-HSA-176187)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  CDC6 association with the ORC (R-HSA-68689)
  Assembly of the pre-replicative complex (R-HSA-68867)
  Orc1 removal from chromatin (R-HSA-68949)
  Activation of the pre-replicative complex (R-HSA-68962)
  E2F-enabled inhibition of pre-replication complex formation (R-HSA-113507)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[1]
Myeloid leukaemia	DISMN944	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[2]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Origin recognition complex subunit 5 (ORC5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Origin recognition complex subunit 5 (ORC5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Origin recognition complex subunit 5 (ORC5).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Origin recognition complex subunit 5 (ORC5).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Origin recognition complex subunit 5 (ORC5).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Origin recognition complex subunit 5 (ORC5).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Origin recognition complex subunit 5 (ORC5).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Origin recognition complex subunit 5 (ORC5).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Origin recognition complex subunit 5 (ORC5).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Origin recognition complex subunit 5 (ORC5).	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Origin recognition complex subunit 5 (ORC5).	[13]

References

• [1] Mutation analysis of the origin recognition complex subunit 5 (ORC5L) gene in adult patients with myeloid leukemias exhibiting deletions of chromosome band 7q22.Hum Genet. 2001 Apr;108(4):304-9. doi: 10.1007/s004390100498.
• [2] PML-like subnuclear bodies, containing XRCC1, juxtaposed to DNA replication-based single-strand breaks.FASEB J. 2019 Feb;33(2):2301-2313. doi: 10.1096/fj.201801379R. Epub 2018 Sep 27.
• [3] Physical mapping of distinct 7q22 deletions in uterine leiomyoma and analysis of a recently annotated 7q22 candidate gene.Cancer Genet Cytogenet. 2007 Apr 15;174(2):116-20. doi: 10.1016/j.cancergencyto.2006.11.018.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [8] 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.
• [9] 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.
• [10] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [14] 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.