Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEO6Y9H)

• DOT Name: AP-1 complex subunit gamma-1 (AP1G1)
• Synonyms: Adaptor protein complex AP-1 subunit gamma-1; Adaptor-related protein complex 1 subunit gamma-1; Clathrin assembly protein complex 1 gamma-1 large chain; Gamma1-adaptin; Golgi adaptor HA1/AP1 adaptin subunit gamma-1
• Gene Name: AP1G1
• Related Disease:
  Complex neurodevelopmental disorder
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Usmani-Riazuddin syndrome, autosomal dominant
  Usmani-Riazuddin syndrome, autosomal recessive
  Head-neck squamous cell carcinoma
• UniProt ID: AP1G1_HUMAN
• PDB ID: 1IU1
• Pfam ID: PF01602 ; PF02883
• Sequence:
  MPAPIRLRELIRTIRTARTQAEEREMIQKECAAIRSSFREEDNTYRCRNVAKLLYMHMLG
  YPAHFGQLECLKLIASQKFTDKRIGYLGAMLLLDERQDVHLLMTNCIKNDLNHSTQFVQG
  LALCTLGCMGSSEMCRDLAGEVEKLLKTSNSYLRKKAALCAVHVIRKVPELMEMFLPATK
  NLLNEKNHGVLHTSVVLLTEMCERSPDMLAHFRKLVPQLVRILKNLIMSGYSPEHDVSGI
  SDPFLQVRILRLLRILGRNDDDSSEAMNDILAQVATNTETSKNVGNAILYETVLTIMDIK
  SESGLRVLAINILGRFLLNNDKNIRYVALTSLLKTVQTDHNAVQRHRSTIVDCLKDLDVS
  IKRRAMELSFALVNGNNIRGMMKELLYFLDSCEPEFKADCASGIFLAAEKYAPSKRWHID
  TIMRVLTTAGSYVRDDAVPNLIQLITNSVEMHAYTVQRLYKAILGDYSQQPLVQVAAWCI
  GEYGDLLVSGQCEEEEPIQVTEDEVLDILESVLISNMSTSVTRGYALTAIMKLSTRFTCT
  VNRIKKVVSIYGSSIDVELQQRAVEYNALFKKYDHMRSALLERMPVMEKVTTNGPTEIVQ
  TNGETEPAPLETKPPPSGPQPTSQANDLLDLLGGNDITPVIPTAPTSKPSSAGGELLDLL
  GDINLTGAPAAAPAPASVPQISQPPFLLDGLSSQPLFNDIAAGIPSITAYSKNGLKIEFT
  FERSNTNPSVTVITIQASNSTELDMTDFVFQAAVPKTFQLQLLSPSSSIVPAFNTGTITQ
  VIKVLNPQKQQLRMRIKLTYNHKGSAMQDLAEVNNFPPQSWQ
• Function: Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. In association with AFTPH/aftiphilin in the aftiphilin/p200/gamma-synergin complex, involved in the trafficking of transferrin from early to recycling endosomes, and the membrane trafficking of furin and the lysosomal enzyme cathepsin D between the trans-Golgi network (TGN) and endosomes.
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Lysosome (hsa04142)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  MHC class II antigen presentation (R-HSA-2132295)
  Lysosome Vesicle Biogenesis (R-HSA-432720)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Nef mediated downregulation of MHC class I complex cell surface expression (R-HSA-164940)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Strong	Autosomal dominant	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Usmani-Riazuddin syndrome, autosomal dominant	DIS4MZ8C	Strong	Autosomal dominant	[4]
Usmani-Riazuddin syndrome, autosomal recessive	DIS23Y9N	Strong	Autosomal recessive	[4]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of AP-1 complex subunit gamma-1 (AP1G1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of AP-1 complex subunit gamma-1 (AP1G1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of AP-1 complex subunit gamma-1 (AP1G1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of AP-1 complex subunit gamma-1 (AP1G1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of AP-1 complex subunit gamma-1 (AP1G1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-1 complex subunit gamma-1 (AP1G1).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of AP-1 complex subunit gamma-1 (AP1G1).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of AP-1 complex subunit gamma-1 (AP1G1).	[14]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of AP-1 complex subunit gamma-1 (AP1G1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of AP-1 complex subunit gamma-1 (AP1G1).	[13]

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] Gamma-adaptin, a novel ubiquitin-interacting adaptor, and Nedd4 ubiquitin ligase control hepatitis B virus maturation.J Biol Chem. 2006 Sep 29;281(39):29297-308. doi: 10.1074/jbc.M603517200. Epub 2006 Jul 25.
• [3] MEG3 promotes liver cancer by activating PI3K/AKT pathway through regulating AP1G1.Eur Rev Med Pharmacol Sci. 2019 Feb;23(4):1459-1467. doi: 10.26355/eurrev_201902_17103.
• [4] De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy. Am J Hum Genet. 2021 Jul 1;108(7):1330-1341. doi: 10.1016/j.ajhg.2021.05.007. Epub 2021 Jun 7.
• [5] AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis.Cancer Lett. 2017 Nov 1;408:33-42. doi: 10.1016/j.canlet.2017.08.012. Epub 2017 Aug 18.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [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] DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line. Physiol Genomics. 2004 Apr 13;17(2):122-9. doi: 10.1152/physiolgenomics.00002.2003.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [15] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.