Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVVD62X)

• DOT Name: Exocyst complex component 6 (EXOC6)
• Synonyms: Exocyst complex component Sec15A; SEC15-like protein 1
• Gene Name: EXOC6
• Related Disease: Non-insulin dependent diabetes
• UniProt ID: EXOC6_HUMAN
• Pfam ID: PF20651 ; PF04091
• Sequence:
  MAENSESLGTVPEHERILQEIESTDTACVGPTLRSVYDDQPNAHKKFMEKLDACIRNHDK
  EIEKMCNFHHQGFVDAITELLKVRTDAEKLKVQVTDTNRRFQDAGKEVIVHTEDIIRCRI
  QQRNITTVVEKLQLCLPVLEMYSKLKEQMSAKRYYSALKTMEQLENVYFPWVSQYRFCQL
  MIENLPKLREDIKEISMSDLKDFLESIRKHSDKIGETAMKQAQHQKTFSVSLQKQNKMKF
  GKNMYINRDRIPEERNETVLKHSLEEEDENEEEILTVQDLVDFSPVYRCLHIYSVLGDEE
  TFENYYRKQRKKQARLVLQPQSNMHETVDGYRRYFTQIVGFFVVEDHILHVTQGLVTRAY
  TDELWNMALSKIIAVLRAHSSYCTDPDLVLELKNLTVIFADTLQGYGFPVNRLFDLLFEI
  RDQYNETLLKKWAGVFRDIFEEDNYSPIPVVNEEEYKIVISKFPFQDPDLEKQSFPKKFP
  MSQSVPHIYIQVKEFIYASLKFSESLHRSSTEIDDMLRKSTNLLLTRTLSSCLLNLIRKP
  HIGLTELVQIIINTTHLEQACKYLEDFITNITNISQETVHTTRLYGLSTFKDARHAAEGE
  IYTKLNQKIDEFVQLADYDWTMSEPDGRASGYLMDLINFLRSIFQVFTHLPGKVAQTACM
  SACQHLSTSLMQMLLDSELKQISMGAVQQFNLDVIQCELFASSEPVPGFQGDTLQLAFID
  LRQLLDLFMVWDWSTYLADYGQPASKYLRVNPNTALTLLEKMKDTSKKNNIFAQFRKNDR
  DKQKLIETVVKQLRSLVNGMSQHM
• Function: Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane. Together with RAB11A, RAB3IP, RAB8A, PARD3, PRKCI, ANXA2, CDC42 and DNMBP promotes transcytosis of PODXL to the apical membrane initiation sites (AMIS), apical surface formation and lumenogenesis.
• Reactome Pathway:
  Insulin processing (R-HSA-264876)
  VxPx cargo-targeting to cilium (R-HSA-5620916)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exocyst complex component 6 (EXOC6).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Exocyst complex component 6 (EXOC6).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Exocyst complex component 6 (EXOC6).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Exocyst complex component 6 (EXOC6).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Exocyst complex component 6 (EXOC6).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Exocyst complex component 6 (EXOC6).	[8]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Exocyst complex component 6 (EXOC6).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Exocyst complex component 6 (EXOC6).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Exocyst complex component 6 (EXOC6).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Exocyst complex component 6 (EXOC6).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Exocyst complex component 6 (EXOC6).	[14]
Manganese	DMKT129	Investigative	Manganese decreases the expression of Exocyst complex component 6 (EXOC6).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Exocyst complex component 6 (EXOC6).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Exocyst complex component 6 (EXOC6).	[11]

References

• [1] Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes.Nat Commun. 2016 Jan 28;7:10531. doi: 10.1038/ncomms10531.
• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] 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.
• [8] 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.
• [9] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [10] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.