Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4DUNVU)

• DOT Name: AP-4 complex subunit epsilon-1 (AP4E1)
• Synonyms: AP-4 adaptor complex subunit epsilon; Adaptor-related protein complex 4 subunit epsilon-1; Epsilon subunit of AP-4; Epsilon-adaptin
• Gene Name: AP4E1
• Related Disease:
  AP-4 deficiency syndrome
  Hereditary spastic paraplegia 51
  Hereditary spastic paraplegia 52
  Cerebral palsy
  Hereditary spastic paraplegia
  Intellectual disability
  Mycobacterium infection
  Obsolete AP4-related intellectual disability and spastic paraplegia
• UniProt ID: AP4E1_HUMAN
• Pfam ID: PF01602 ; PF14807
• Sequence:
  MSDIVEKTLTALPGLFLQNQPGGGPAAAKASFSSRLGSLVRGITALTSKHEEEKLIQQEL
  SSLKATVSAPTTTLKMMKECMVRLIYCEMLGYDASFGYIHAIKLAQQGNLLEKRVGYLAV
  SLFLHESHELLLLLVNTVVKDLQSTNLVEVCMALTVVSQIFPCEMIPAVLPLIEDKLQHS
  KEIVRRKAVLALYKFHLIAPNQVQHIHIKFRKALCDRDVGVMAASLHIYLRMIKENSSGY
  KDLTGSFVTILKQVVGGKLPVEFNYHSVPAPWLQIQLLRILGLLGKDDQRTSELMYDVLD
  ESLRRAELNHNVTYAILFECVHTVYSIYPKSELLEKAAKCIGKFVLSPKINLKYLGLKAL
  TYVIQQDPTLALQHQMTIIECLDHPDPIIKRETLELLYRITNAQNITVIVQKMLEYLHQS
  KEEYVIVNLVGKIAELAEKYAPDNAWFIQTMNAVFSVGGDVMHPDIPNNFLRLLAEGFDD
  ETEDQQLRLYAVQSYLTLLDMENVFYPQRFLQVMSWVLGEYSYLLDKETPEEVIAKLYKL
  LMNDSVSSETKAWLIAAVTKLTSQAHSSNTVERLIHEFTISLDTCMRQHAFELKHLHENV
  ELMKSLLPVDRSCEDLVVDASLSFLDGFVAEGLSQGAAPYKPPHQRQEEKLSQEKVLNFE
  PYGLSFSSSGFTGRQSPAGISLGSDVSGNSAETGLKETNSLKLEGIKKLWGKEGYLPKKE
  SKTGDESGALPVPQESIMENVDQAITKKDQSQVLTQSKEEKEKQLLASSLFVGLGSESTI
  NLLGKADTVSHKFRRKSKVKEAKSGETTSTHNMTCSSFSSLSNVAYEDDYYSNTLHDTGD
  KELKKFSLTSELLDSESLTELPLVEKFSYCSLSTPSLFANNNMEIFHPPQSTAASVAKES
  SLASSFLEETTEYIHSNAMEVCNNETISVSSYKIWKDDCLLMVWSVTNKSGLELKSADLE
  IFPAENFKVTEQPGCCLPVMEAESTKSFQYSVQIEKPFTEGNLTGFISYHMMDTHSAQLE
  FSVNLSLLDFIRPLKISSDDFGKLWLSFANDVKQNVKMSESQAALPSALKTLQQKLRLHI
  IEIIGNEGLLACQLLPSIPCLLHCRVHADVLALWFRSSCSTLPDYLLYQCQKVMEGS
• Function: Component of the adaptor protein complex 4 (AP-4). Adaptor protein complexes are vesicle coat components involved both in vesicle formation and cargo selection. They control the vesicular transport of proteins in different trafficking pathways. AP-4 forms a non clathrin-associated coat on vesicles departing the trans-Golgi network (TGN) and may be involved in the targeting of proteins from the trans-Golgi network (TGN) to the endosomal-lysosomal system. It is also involved in protein sorting to the basolateral membrane in epithelial cells and the proper asymmetric localization of somatodendritic proteins in neurons. AP-4 is involved in the recognition and binding of tyrosine-based sorting signals found in the cytoplasmic part of cargos, but may also recognize other types of sorting signal (Probable).
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Lysosome Vesicle Biogenesis (R-HSA-432720)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
AP-4 deficiency syndrome	DISCF43Z	Definitive	Autosomal recessive	[1]
Hereditary spastic paraplegia 51	DIS3DFPG	Definitive	Autosomal recessive	[2]
Hereditary spastic paraplegia 52	DISQ4O7P	Definitive	Genetic Variation	[3]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[4]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Mycobacterium infection	DISNSMUD	Strong	Genetic Variation	[6]
Obsolete AP4-related intellectual disability and spastic paraplegia	DISFYNHU	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	AP-4 complex subunit epsilon-1 (AP4E1) affects the response to substance of Doxorubicin.	[17]

7 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 AP-4 complex subunit epsilon-1 (AP4E1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of AP-4 complex subunit epsilon-1 (AP4E1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of AP-4 complex subunit epsilon-1 (AP4E1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of AP-4 complex subunit epsilon-1 (AP4E1).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of AP-4 complex subunit epsilon-1 (AP4E1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of AP-4 complex subunit epsilon-1 (AP4E1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of AP-4 complex subunit epsilon-1 (AP4E1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of AP-4 complex subunit epsilon-1 (AP4E1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of AP-4 complex subunit epsilon-1 (AP4E1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of AP-4 complex subunit epsilon-1 (AP4E1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of AP-4 complex subunit epsilon-1 (AP4E1).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability. J Med Genet. 2011 Feb;48(2):141-4. doi: 10.1136/jmg.2010.082263. Epub 2010 Oct 23.
• [3] Generation and characterization of six human induced pluripotent stem cell lines (iPSC) from three families with AP4B1-associated hereditary spastic paraplegia (SPG47).Stem Cell Res. 2019 Oct;40:101575. doi: 10.1016/j.scr.2019.101575. Epub 2019 Sep 11.
• [4] Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011 Jun 10;88(6):788-795. doi: 10.1016/j.ajhg.2011.04.019. Epub 2011 May 27.
• [5] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [6] A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease.PLoS One. 2013;8(3):e58286. doi: 10.1371/journal.pone.0058286. Epub 2013 Mar 5.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] 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.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] 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.
• [13] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [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] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.