Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJLI0IM)

• DOT Name: AP-3 complex subunit delta-1 (AP3D1)
• Synonyms: AP-3 complex subunit delta; Adaptor-related protein complex 3 subunit delta-1; Delta-adaptin
• Gene Name: AP3D1
• Related Disease:
  Epilepsy
  Hantavirus infection
  Hermansky-Pudlak syndrome 2
  Inherited bleeding disorder, platelet-type
  Myocardial infarction
  Nervous system disease
  Ocular albinism
  Oculocutaneous albinism
  Platelet storage pool deficiency
  Hermansky-Pudlak syndrome 10
  Albinism
  Hermansky-Pudlak syndrome
• UniProt ID: AP3D1_HUMAN
• PDB ID: 4AFI
• Pfam ID: PF01602 ; PF06375
• Sequence:
  MALKMVKGSIDRMFDKNLQDLVRGIRNHKEDEAKYISQCIDEIKQELKQDNIAVKANAVC
  KLTYLQMLGYDISWAAFNIIEVMSASKFTFKRIGYLAASQSFHEGTDVIMLTTNQIRKDL
  SSPSQYDTGVALTGLSCFVTPDLARDLANDIMTLMSHTKPYIRKKAVLIMYKVFLKYPES
  LRPAFPRLKEKLEDPDPGVQSAAVNVICELARRNPKNYLSLAPLFFKLMTSSTNNWVLIK
  IIKLFGALTPLEPRLGKKLIEPLTNLIHSTSAMSLLYECVNTVIAVLISLSSGMPNHSAS
  IQLCVQKLRILIEDSDQNLKYLGLLAMSKILKTHPKSVQSHKDLILQCLDDKDESIRLRA
  LDLLYGMVSKKNLMEIVKKLMTHVDKAEGTTYRDELLTKIIDICSQSNYQYITNFEWYIS
  ILVELTRLEGTRHGHLIAAQMLDVAIRVKAIRKFAVSQMSALLDSAHLLASSTQRNGICE
  VLYAAAWICGEFSEHLQEPHHTLEAMLRPRVTTLPGHIQAVYVQNVVKLYASILQQKEQA
  GEAEGAQAVTQLMVDRLPQFVQSADLEVQERASCILQLVKHIQKLQAKDVPVAEEVSALF
  AGELNPVAPKAQKKVPVPEGLDLDAWINEPLSDSESEDERPRAVFHEEEQRRPKHRPSEA
  DEEELARRREARKQEQANNPFYIKSSPSPQKRYQDTPGVEHIPVVQIDLSVPLKVPGLPM
  SDQYVKLEEERRHRQKLEKDKRRKKRKEKEKKGKRRHSSLPTESDEDIAPAQQVDIVTEE
  MPENALPSDEDDKDPNDPYRALDIDLDKPLADSEKLPIQKHRNTETSKSPEKDVPMVEKK
  SKKPKKKEKKHKEKERDKEKKKEKEKKKSPKPKKKKHRKEKEERTKGKKKSKKQPPGSEE
  AAGEPVQNGAPEEEQLPPESSYSLLAENSYVKMTCDIRGSLQEDSQVTVAIVLENRSSSI
  LKGMELSVLDSLNARMARPQGSSVHDGVPVPFQLPPGVSNEAQYVFTIQSIVMAQKLKGT
  LSFIAKNDEGATHEKLDFRLHFSCSSYLITTPCYSDAFAKLLESGDLSMSSIKVDGIRMS
  FQNLLAKICFHHHFSVVERVDSCASMYSRSIQGHHVCLLVKKGENSVSVDGKCSDSTLLS
  NLLEEMKATLAKC
• Function: Part of the AP-3 complex, an adaptor-related complex which is not clathrin-associated. The complex is associated with the Golgi region as well as more peripheral structures. It facilitates the budding of vesicles from the Golgi membrane and may be directly involved in trafficking to lysosomes. Involved in process of CD8+ T-cell and NK cell degranulation. In concert with the BLOC-1 complex, AP-3 is required to target cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals.
• Tissue Specificity: Present in all adult tissues examined with the highest levels in skeletal muscle, heart, pancreas and testis.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Genetic Variation	[1]
Hantavirus infection	DISZFTMH	Strong	Genetic Variation	[2]
Hermansky-Pudlak syndrome 2	DISQMA1H	Strong	Biomarker	[3]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Biomarker	[4]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[5]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[2]
Ocular albinism	DIS5IHK1	Strong	Genetic Variation	[2]
Oculocutaneous albinism	DISJS7CU	Strong	Biomarker	[1]
Platelet storage pool deficiency	DISHODOH	Strong	Genetic Variation	[2]
Hermansky-Pudlak syndrome 10	DISV6R72	Moderate	Autosomal recessive	[6]
Albinism	DIS5D82I	Limited	Biomarker	[2]
Hermansky-Pudlak syndrome	DISCY0HQ	Limited	Genetic Variation	[1]

9 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-3 complex subunit delta-1 (AP3D1).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of AP-3 complex subunit delta-1 (AP3D1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of AP-3 complex subunit delta-1 (AP3D1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-3 complex subunit delta-1 (AP3D1).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of AP-3 complex subunit delta-1 (AP3D1).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of AP-3 complex subunit delta-1 (AP3D1).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of AP-3 complex subunit delta-1 (AP3D1).	[16]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of AP-3 complex subunit delta-1 (AP3D1).	[18]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of AP-3 complex subunit delta-1 (AP3D1).	[19]

4 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 AP-3 complex subunit delta-1 (AP3D1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of AP-3 complex subunit delta-1 (AP3D1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of AP-3 complex subunit delta-1 (AP3D1).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of AP-3 complex subunit delta-1 (AP3D1).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of AP-3 complex subunit delta-1 (AP3D1).	[14]

References

• [1] Biallelic mutations in AP3D1 cause Hermansky-Pudlak syndrome type 10 associated with immunodeficiency and seizure disorder.Eur J Med Genet. 2019 Nov;62(11):103583. doi: 10.1016/j.ejmg.2018.11.017. Epub 2018 Nov 22.
• [2] Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016 Feb 25;127(8):997-1006. doi: 10.1182/blood-2015-09-671636. Epub 2016 Jan 7.
• [3] Gravity receptor function in mice with graded otoconial deficiencies.Hear Res. 2004 May;191(1-2):34-40. doi: 10.1016/j.heares.2004.01.008.
• [4] A new type of syndromic albinism associated with mutations in AP3D1.Pigment Cell Melanoma Res. 2017 Jan;30(1):5-7. doi: 10.1111/pcmr.12543. Epub 2016 Nov 30.
• [5] A genome-wide association study identifies PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for myocardial infarction in Japanese.Eur J Hum Genet. 2015 Mar;23(3):374-80. doi: 10.1038/ejhg.2014.110. Epub 2014 Jun 11.
• [6] 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.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [13] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] 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.
• [17] 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.
• [18] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [19] 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.