Details of Drug Off-Target (DOT)

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

• DOT Name: Anaphase-promoting complex subunit 5 (ANAPC5)
• Synonyms: APC5; Cyclosome subunit 5
• Gene Name: ANAPC5
• Related Disease:
  Cytomegalovirus infection
  Familial adenomatous polyposis
  Schizophrenia
• UniProt ID: APC5_HUMAN
• PDB ID: 4UI9; 5A31; 5G04; 5G05; 5KHR; 5KHU; 5L9T; 5L9U; 5LCW; 6Q6G; 6Q6H; 6TLJ; 6TM5; 6TNT; 7QE7; 8PKP; 8TAR; 8TAU
• Pfam ID: PF12862 ; PF21371
• Sequence:
  MASVHESLYFNPMMTNGVVHANVFGIKDWVTPYKIAVLVLLNEMSRTGEGAVSLMERRRL
  NQLLLPLLQGPDITLSKLYKLIEESCPQLANSVQIRIKLMAEGELKDMEQFFDDLSDSFS
  GTEPEVHKTSVVGLFLRHMILAYSKLSFSQVFKLYTALQQYFQNGEKKTVEDADMELTSR
  DEGERKMEKEELDVSVREEEVSCSGPLSQKQAEFFLSQQASLLKNDETKALTPASLQKEL
  NNLLKFNPDFAEAHYLSYLNNLRVQDVFSSTHSLLHYFDRLILTGAESKSNGEEGYGRSL
  RYAALNLAALHCRFGHYQQAELALQEAIRIAQESNDHVCLQHCLSWLYVLGQKRSDSYVL
  LEHSVKKAVHFGLPYLASLGIQSLVQQRAFAGKTANKLMDALKDSDLLHWKHSLSELIDI
  SIAQKTAIWRLYGRSTMALQQAQMLLSMNSLEAVNAGVQQNNTESFAVALCHLAELHAEQ
  GCFAAASEVLKHLKERFPPNSQHAQLWMLCDQKIQFDRAMNDGKYHLADSLVTGITALNS
  IEGVYRKAVVLQAQNQMSEAHKLLQKLLVHCQKLKNTEMVISVLLSVAELYWRSSSPTIA
  LPMLLQALALSKEYRLQYLASETVLNLAFAQLILGIPEQALSLLHMAIEPILADGAILDK
  GRAMFLVAKCQVASAASYDQPKKAEALEAAIENLNEAKNYFAKVDCKERIRDVVYFQARL
  YHTLGKTQERNRCAMLFRQLHQELPSHGVPLINHL
• Function: Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Ubiquitin mediated proteolysis (hsa04120)
  IL-17 sig.ling pathway (hsa04657)
  Progesterone-mediated oocyte maturation (hsa04914)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  APC/C (R-HSA-174048)
  Autodegradation of Cdh1 by Cdh1 (R-HSA-174084)
  APC/C (R-HSA-174154)
  APC/C (R-HSA-174178)
  Cdc20 (R-HSA-174184)
  Conversion from APC/C (R-HSA-176407)
  Regulation of APC/C activators between G1/S and early anaphase (R-HSA-176408)
  APC/C (R-HSA-176409)
  Phosphorylation of the APC/C (R-HSA-176412)
  APC-Cdc20 mediated degradation of Nek2A (R-HSA-179409)
  Separation of Sister Chromatids (R-HSA-2467813)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Assembly of the pre-replicative complex (R-HSA-68867)
  CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Aberrant regulation of mitotic exit in cancer due to RB1 defects (R-HSA-9687136)
  Antigen processing (R-HSA-983168)
  Inactivation of APC/C via direct inhibition of the APC/C complex (R-HSA-141430)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[1]
Familial adenomatous polyposis	DISW53RE	Limited	Genetic Variation	[2]
Schizophrenia	DISSRV2N	No Known	Unknown	[3]

12 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 Anaphase-promoting complex subunit 5 (ANAPC5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[9]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[14]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[15]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Anaphase-promoting complex subunit 5 (ANAPC5).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Anaphase-promoting complex subunit 5 (ANAPC5).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Anaphase-promoting complex subunit 5 (ANAPC5).	[13]

References

• [1] Inactivation and disassembly of the anaphase-promoting complex during human cytomegalovirus infection is associated with degradation of the APC5 and APC4 subunits and does not require UL97-mediated phosphorylation of Cdh1.J Virol. 2010 Oct;84(20):10832-43. doi: 10.1128/JVI.01260-10. Epub 2010 Aug 4.
• [2] APC transcription studies and molecular diagnosis of familial adenomatous polyposis.Eur J Hum Genet. 2020 Jan;28(1):118-121. doi: 10.1038/s41431-019-0486-2. Epub 2019 Aug 5.
• [3] Rare damaging variants in DNA repair and cell cycle pathways are associated with hippocampal and cognitive dysfunction: a combined genetic imaging study in first-episode treatment-naive patients with schizophrenia. Transl Psychiatry. 2017 Feb 14;7(2):e1028. doi: 10.1038/tp.2016.291.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [13] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [15] 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.
• [16] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.