Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYAVVJ6)

• DOT Name: DnaJ homolog subfamily C member 13 (DNAJC13)
• Synonyms: Required for receptor-mediated endocytosis 8; RME-8
• Gene Name: DNAJC13
• Related Disease:
  Breast cancer
  Breast carcinoma
  DiGeorge syndrome
  Essential tremor
  Lafora disease
  Late-onset Parkinson disease
  Lewy body dementia
  Nephronophthisis 3
  Normal pressure hydrocephalus
  Retinopathy
  Senior-Loken syndrome
  Sjogren-Larsson syndrome
  Obsolete hereditary late onset Parkinson disease
  Parkinsonian disorder
• UniProt ID: DJC13_HUMAN
• Pfam ID: PF00226 ; PF14237 ; PF19432
• Sequence:
  MNIIRENKDLACFYTTKHSWRGKYKRVFSVGTHAITTYNPNTLEVTNQWPYGDICSISPV
  GKGQGTEFNLTFRKGSGKKSETLKFSTEHRTELLTEALRFRTDFSEGKITGRRYNCYKHH
  WSDSRKPVILEVTPGGFDQINPATNRVLCSYDYRNIEGFVDLSDYQGGFCILYGGFSRLH
  LFASEQREEIIKSAIDHAGNYIGISLRIRKEPLEFEQYLNLRFGKYSTDESITSLAEFVV
  QKISPRHSEPVKRVLALTETCLVERDPATYNIATLKPLGEVFALVCDSENPQLFTIEFIK
  GQVRKYSSTERDSLLASLLDGVRASGNRDVCVKMTPTHKGQRWGLLSMPVDEEVESLHLR
  FLATPPNGNFADAVFRFNANISYSGVLHAVTQDGLFSENKEKLINNAITALLSQEGDVVA
  SNAELESQFQAVRRLVASKAGFLAFTQLPKFRERLGVKVVKALKRSNNGIIHAAVDMLCA
  LMCPMHDDYDLRQEQLNKASLLSSKKFLENLLEKFNSHVDHGTGALVISSLLDFLTFALC
  APYSETTEGQQFDMLLEMVASNGRTLFKLFQHPSMAIIKGAGLVMKAIIEEGDKEIATKM
  QELALSEGALPRHLHTAMFTISSDQRMLTNRQLSRHLVGLWTADNATATNLLKRILPPGL
  LAYLESSDLVPEKDADRMHVRDNVKIAMDQYGKFNKVPEWQRLAGKAAKEVEKFAKEKVD
  LVLMHWRDRMGIAQKENINQKPVVLRKRRQRIKIEANWDLFYYRFGQDHARSNLIWNFKT
  REELKDTLESEMRAFNIDRELGSANVISWNHHEFEVKYECLAEEIKIGDYYLRLLLEEDE
  NEESGSIKRSYEFFNELYHRFLLTPKVNMKCLCLQALAIVYGRCHEEIGPFTDTRYIIGM
  LERCTDKLERDRLILFLNKLILNKKNVKDLMDSNGIRILVDLLTLAHLHVSRATVPLQSN
  VIEAAPDMKRESEKEWYFGNADKERSGPYGFHEMQELWTKGMLNAKTRCWAQGMDGWRPL
  QSIPQLKWCLLASGQAVLNETDLATLILNMLITMCGYFPSRDQDNAIIRPLPKVKRLLSD
  STCLPHIIQLLLTFDPILVEKVAILLYHIMQDNPQLPRLYLSGVFFFIMMYTGSNVLPVA
  RFLKYTHTKQAFKSEETKGQDIFQRSILGHILPEAMVCYLENYEPEKFSEIFLGEFDTPE
  AIWSSEMRRLMIEKIAAHLADFTPRLQSNTRALYQYCPIPIINYPQLENELFCNIYYLKQ
  LCDTLRFPDWPIKDPVKLLKDTLDAWKKEVEKKPPMMSIDDAYEVLNLPQGQGPHDESKI
  RKAYFRLAQKYHPDKNPEGRDMFEKVNKAYEFLCTKSAKIVDGPDPENIILILKTQSILF
  NRHKEDLQPYKYAGYPMLIRTITMETSDDLLFSKESPLLPAATELAFHTVNCSALNAEEL
  RRENGLEVLQEAFSRCVAVLTRASKPSDMSVQVCGYISKCYSVAAQFEECREKITEMPSI
  IKDLCRVLYFGKSIPRVAALGVECVSSFAVDFWLQTHLFQAGILWYLLGFLFNYDYTLEE
  SGIQKSEETNQQEVANSLAKLSVHALSRLGGYLAEEQATPENPTIRKSLAGMLTPYVARK
  LAVASVTEILKMLNSNTESPYLIWNNSTRAELLEFLESQQENMIKKGDCDKTYGSEFVYS
  DHAKELIVGEIFVRVYNEVPTFQLEVPKAFAASLLDYIGSQAQYLHTFMAITHAAKVESE
  QHGDRLPRVEMALEALRNVIKYNPGSESECIGHFKLIFSLLRVHGAGQVQQLALEVVNIV
  TSNQDCVNNIAESMVLSSLLALLHSLPSSRQLVLETLYALTSSTKIIKEAMAKGALIYLL
  DMFCNSTHPQVRAQTAELFAKMTADKLIGPKVRITLMKFLPSVFMDAMRDNPEAAVHIFE
  GTHENPELIWNDNSRDKVSTTVREMMLEHFKNQQDNPEANWKLPEDFAVVFGEAEGELAV
  GGVFLRIFIAQPAWVLRKPREFLIALLEKLTELLEKNNPHGETLETLTMATVCLFSAQPQ
  LADQVPPLGHLPKVIQAMNHRNNAIPKSAIRVIHALSENELCVRAMASLETIGPLMNGMK
  KRADTVGLACEAINRMFQKEQSELVAQALKADLVPYLLKLLEGIGLENLDSPAATKAQIV
  KALKAMTRSLQYGEQVNEILCRSSVWSAFKDQKHDLFISESQTAGYLTGPGVAGYLTAGT
  STSVMSNLPPPVDHEAGDLGYQT
• Function: Involved in membrane trafficking through early endosomes, such as the early endosome to recycling endosome transport implicated in the recycling of transferrin and the early endosome to late endosome transport implicated in degradation of EGF and EGFR. Involved in the regulation of endosomal membrane tubulation and regulates the dynamics of SNX1 on the endosomal membrane; via association with WASHC2 may link the WASH complex to the retromer SNX-BAR subcomplex.
• Reactome Pathway: Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
DiGeorge syndrome	DIST1RKO	Strong	Biomarker	[2]
Essential tremor	DIS7GBKQ	Strong	Genetic Variation	[3]
Lafora disease	DIS83JHH	Strong	Genetic Variation	[4]
Late-onset Parkinson disease	DIS9IOUI	Strong	Genetic Variation	[5]
Lewy body dementia	DISAE66J	Strong	Genetic Variation	[4]
Nephronophthisis 3	DIS4CC6R	moderate	Genetic Variation	[6]
Normal pressure hydrocephalus	DISOEFO9	moderate	Biomarker	[6]
Retinopathy	DISB4B0F	moderate	Biomarker	[6]
Senior-Loken syndrome	DISGBSGP	moderate	Biomarker	[6]
Sjogren-Larsson syndrome	DISP943Y	moderate	Genetic Variation	[6]
Obsolete hereditary late onset Parkinson disease	DISCT6PQ	Supportive	Autosomal dominant	[7]
Parkinsonian disorder	DISHGY45	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[14]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[15]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DnaJ homolog subfamily C member 13 (DNAJC13).	[17]

References

• [1] RME-8 regulates trafficking of the epidermal growth factor receptor.FEBS Lett. 2008 Mar 19;582(6):961-6. doi: 10.1016/j.febslet.2008.02.042. Epub 2008 Feb 26.
• [2] Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature.Mov Disord. 2017 Nov;32(11):1504-1523. doi: 10.1002/mds.27193.
• [3] VPS35 and DNAJC13 disease-causing variants in essential tremor.Eur J Hum Genet. 2015 Jun;23(6):887-8. doi: 10.1038/ejhg.2014.164. Epub 2014 Aug 13.
• [4] DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients.Eur J Neurol. 2015 Sep;22(9):1323-5. doi: 10.1111/ene.12770.
• [5] DNAJC13 genetic variants in parkinsonism.Mov Disord. 2015 Feb;30(2):273-8. doi: 10.1002/mds.26064. Epub 2014 Nov 12.
• [6] Candidate gene analysis of KIAA0678 encoding a DnaJ-like protein for adolescent nephronophthisis and Senior-Lken syndrome type 3.Cytogenet Genome Res. 2002;97(3-4):163-6. doi: 10.1159/000066617.
• [7] DNAJC13 mutations in Parkinson disease. Hum Mol Genet. 2014 Apr 1;23(7):1794-801. doi: 10.1093/hmg/ddt570. Epub 2013 Nov 11.
• [8] DNAJC13 p.Asn855Ser, implicated in familial parkinsonism, alters membrane dynamics of sorting nexin 1.Neurosci Lett. 2019 Jul 27;706:114-122. doi: 10.1016/j.neulet.2019.04.043. Epub 2019 May 11.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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.
• [15] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [16] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.