Details of Drug Off-Target (DOT)

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

• DOT Name: AP-4 complex subunit beta-1 (AP4B1)
• Synonyms: AP-4 adaptor complex subunit beta; Adaptor-related protein complex 4 subunit beta-1; Beta subunit of AP-4; Beta4-adaptin
• Gene Name: AP4B1
• Related Disease:
  AP-4 deficiency syndrome
  Hereditary spastic paraplegia 2
  Breast carcinoma
  Cerebral palsy
  Hereditary spastic paraplegia 47
  Intellectual disability
  Microcephaly
  Spastic quadriplegic cerebral palsy
  Squamous cell carcinoma
  Vascular purpura
  Hereditary spastic paraplegia
  Obsolete AP4-related intellectual disability and spastic paraplegia
  Isolated congenital microcephaly
  Lung cancer
  Lung carcinoma
• UniProt ID: AP4B1_HUMAN
• PDB ID: 2MJ7
• Pfam ID: PF01602 ; PF09066
• Sequence:
  MPYLGSEDVVKELKKALCNPHIQADRLRYRNVIQRVIRYMTQGLDMSGVFMEMVKASATV
  DIVQKKLVYLYMCTYAPLKPDLALLAINTLCKDCSDPNPMVRGLALRSMCSLRMPGVQEY
  IQQPILNGLRDKASYVRRVAVLGCAKMHNLHGDSEVDGALVNELYSLLRDQDPIVVVNCL
  RSLEEILKQEGGVVINKPIAHHLLNRMSKLDQWGQAEVLNFLLRYQPRSEEELFDILNLL
  DSFLKSSSPGVVMGATKLFLILAKMFPHVQTDVLVRVKGPLLAACSSESRELCFVALCHV
  RQILHSLPGHFSSHYKKFFCSYSEPHYIKLQKVEVLCELVNDENVQQVLEELRGYCTDVS
  ADFAQAAIFAIGGIARTYTDQCVQILTELLGLRQEHITTVVVQTFRDLVWLCPQCTEAVC
  QALPGCEENIQDSEGKQALIWLLGVHGERIPNAPYVLEDFVENVKSETFPAVKMELLTAL
  LRLFLSRPAECQDMLGRLLYYCIEEEKDMAVRDRGLFYYRLLLVGIDEVKRILCSPKSDP
  TLGLLEDPAERPVNSWASDFNTLVPVYGKAHWATISKCQGAERCDPELPKTSSFAASGPL
  IPEENKERVQELPDSGALMLVPNRQLTADYFEKTWLSLKVAHQQVLPWRGEFHPDTLQMA
  LQVVNIQTIAMSRAGSRPWKAYLSAQDDTGCLFLTELLLEPGNSEMQISVKQNEARTETL
  NSFISVLETVIGTIEEIKS
• 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

15 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 2	DIS0TD1L	Definitive	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Cerebral palsy	DIS82ODL	Strong	Biomarker	[4]
Hereditary spastic paraplegia 47	DIS25W9X	Strong	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Microcephaly	DIS2GRD8	Strong	CausalMutation	[7]
Spastic quadriplegic cerebral palsy	DISBJRHC	Strong	Genetic Variation	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[9]
Vascular purpura	DIS6ZZMF	Strong	Biomarker	[10]
Hereditary spastic paraplegia	DISGZQV1	moderate	Genetic Variation	[11]
Obsolete AP4-related intellectual disability and spastic paraplegia	DISFYNHU	Supportive	Autosomal recessive	[7]
Isolated congenital microcephaly	DISUXHZ6	Disputed	Genetic Variation	[6]
Lung cancer	DISCM4YA	Limited	Altered Expression	[12]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of AP-4 complex subunit beta-1 (AP4B1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of AP-4 complex subunit beta-1 (AP4B1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of AP-4 complex subunit beta-1 (AP4B1).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of AP-4 complex subunit beta-1 (AP4B1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of AP-4 complex subunit beta-1 (AP4B1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of AP-4 complex subunit beta-1 (AP4B1).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of AP-4 complex subunit beta-1 (AP4B1).	[19]

1 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 AP-4 complex subunit beta-1 (AP4B1).	[17]

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] Locus and allelic heterogeneity in five families with hereditary spastic paraplegia.J Hum Genet. 2019 Jan;64(1):17-21. doi: 10.1038/s10038-018-0523-y. Epub 2018 Oct 18.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population.Mol Biol Rep. 2013 Nov;40(11):6459-67. doi: 10.1007/s11033-013-2761-6. Epub 2013 Sep 25.
• [5] 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.
• [6] A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocular anomalies.Am J Med Genet A. 2018 Apr;176(4):985-991. doi: 10.1002/ajmg.a.38628. Epub 2018 Feb 12.
• [7] Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47). Neurogenetics. 2012 Feb;13(1):73-6. doi: 10.1007/s10048-012-0314-0.
• [8] An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome.Eur J Hum Genet. 2015 Feb;23(2):256-9. doi: 10.1038/ejhg.2014.73. Epub 2014 Apr 30.
• [9] Metastatic growth of squamous cell carcinomas is correlated with upregulation and redistribution of hemidesmosomal components.Cell Tissue Res. 2001 Dec;306(3):399-408. doi: 10.1007/s004410100462. Epub 2001 Oct 23.
• [10] Clinical and genetic characterization of AP4B1-associated SPG47.Am J Med Genet A. 2018 Feb;176(2):311-318. doi: 10.1002/ajmg.a.38561. Epub 2017 Nov 28.
• [11] Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance.J Neurol Sci. 2012 Jul 15;318(1-2):1-18. doi: 10.1016/j.jns.2012.03.025. Epub 2012 May 1.
• [12] New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer.Biomed Pharmacother. 2017 Dec;96:659-666. doi: 10.1016/j.biopha.2017.10.041. Epub 2017 Nov 6.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] 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.
• [15] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.