Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYTIH5Q)

• DOT Name: AP-3 complex subunit beta-1 (AP3B1)
• Synonyms: Adaptor protein complex AP-3 subunit beta-1; Adaptor-related protein complex 3 subunit beta-1; Beta-3A-adaptin; Clathrin assembly protein complex 3 beta-1 large chain
• Gene Name: AP3B1
• Related Disease:
  Hermansky-Pudlak syndrome 2
  Acute megakaryoblastic leukemia
  Albinism
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Chediak-Higashi syndrome
  Coagulation defect
  Colorectal carcinoma
  Griscelli syndrome
  Hantavirus infection
  Knee osteoarthritis
  Leukopenia
  Nephropathy
  Ocular albinism
  Oculocutaneous albinism
  Platelet storage pool deficiency
  Polyp
  Pulmonary disease
  Pulmonary fibrosis
  Usher syndrome type 1B
  Bartter disease type 3
  Bartter syndrome
  Hemophagocytic syndrome
  Nephrocalcinosis
  Acute myelogenous leukaemia
  Asthma
• UniProt ID: AP3B1_HUMAN
• Pfam ID: PF01602 ; PF14796 ; PF14797
• Sequence:
  MSSNSFPYNEQSGGGEATELGQEATSTISPSGAFGLFSSDLKKNEDLKQMLESNKDSAKL
  DAMKRIVGMIAKGKNASELFPAVVKNVASKNIEIKKLVYVYLVRYAEEQQDLALLSISTF
  QRALKDPNQLIRASALRVLSSIRVPIIVPIMMLAIKEASADLSPYVRKNAAHAIQKLYSL
  DPEQKEMLIEVIEKLLKDKSTLVAGSVVMAFEEVCPDRIDLIHKNYRKLCNLLVDVEEWG
  QVVIIHMLTRYARTQFVSPWKEGDELEDNGKNFYESDDDQKEKTDKKKKPYTMDPDHRLL
  IRNTKPLLQSRNAAVVMAVAQLYWHISPKSEAGIISKSLVRLLRSNREVQYIVLQNIATM
  SIQRKGMFEPYLKSFYVRSTDPTMIKTLKLEILTNLANEANISTLLREFQTYVKSQDKQF
  AAATIQTIGRCATNILEVTDTCLNGLVCLLSNRDEIVVAESVVVIKKLLQMQPAQHGEII
  KHMAKLLDSITVPVARASILWLIGENCERVPKIAPDVLRKMAKSFTSEDDLVKLQILNLG
  AKLYLTNSKQTKLLTQYILNLGKYDQNYDIRDRTRFIRQLIVPNVKSGALSKYAKKIFLA
  QKPAPLLESPFKDRDHFQLGTLSHTLNIKATGYLELSNWPEVAPDPSVRNVEVIELAKEW
  TPAGKAKQENSAKKFYSESEEEEDSSDSSSDSESESGSESGEQGESGEEGDSNEDSSEDS
  SSEQDSESGRESGLENKRTAKRNSKAKGKSDSEDGEKENEKSKTSDSSNDESSSIEDSSS
  DSESESEPESESESRRVTKEKEKKTKQDRTPLTKDVSLLDLDDFNPVSTPVALPTPALSP
  SLMADLEGLHLSTSSSVISVSTPAFVPTKTHVLLHRMSGKGLAAHYFFPRQPCIFGDKMV
  SIQITLNNTTDRKIENIHIGEKKLPIGMKMHVFNPIDSLEPEGSITVSMGIDFCDSTQTA
  SFQLCTKDDCFNVNIQPPVGELLLPVAMSEKDFKKEQGVLTGMNETSAVIIAAPQNFTPS
  VIFQKVVNVANVGAVPSGQDNIHRFAAKTVHSGSLMLVTVELKEGSTAQLIINTEKTVIG
  SVLLRELKPVLSQG
• Function: Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) 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. AP-3 appears to be involved in the sorting of a subset of transmembrane proteins targeted to lysosomes and lysosome-related organelles. 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: Ubiquitously expressed.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hermansky-Pudlak syndrome 2	DISQMA1H	Definitive	Autosomal recessive	[1]
Acute megakaryoblastic leukemia	DIS0JX3M	Strong	Altered Expression	[2]
Albinism	DIS5D82I	Strong	Genetic Variation	[3]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Chediak-Higashi syndrome	DISPJLLO	Strong	Biomarker	[6]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Griscelli syndrome	DISTHCOQ	Strong	Genetic Variation	[9]
Hantavirus infection	DISZFTMH	Strong	Biomarker	[10]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[11]
Leukopenia	DISJMBMM	Strong	Biomarker	[12]
Nephropathy	DISXWP4P	Strong	Biomarker	[13]
Ocular albinism	DIS5IHK1	Strong	Genetic Variation	[9]
Oculocutaneous albinism	DISJS7CU	Strong	Genetic Variation	[7]
Platelet storage pool deficiency	DISHODOH	Strong	Genetic Variation	[7]
Polyp	DISRSLYF	Strong	Biomarker	[8]
Pulmonary disease	DIS6060I	Strong	Biomarker	[12]
Pulmonary fibrosis	DISQKVLA	Strong	Genetic Variation	[14]
Usher syndrome type 1B	DISWTUHR	Strong	Genetic Variation	[9]
Bartter disease type 3	DISJJPTS	moderate	Biomarker	[15]
Bartter syndrome	DIS7D44B	moderate	Genetic Variation	[15]
Hemophagocytic syndrome	DIS3TMN4	moderate	Biomarker	[16]
Nephrocalcinosis	DIS5ZVJP	moderate	Biomarker	[15]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[17]
Asthma	DISW9QNS	Limited	Genetic Variation	[18]

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 beta-1 (AP3B1).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of AP-3 complex subunit beta-1 (AP3B1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-3 complex subunit beta-1 (AP3B1).	[21]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of AP-3 complex subunit beta-1 (AP3B1).	[20]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of AP-3 complex subunit beta-1 (AP3B1).	[22]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of AP-3 complex subunit beta-1 (AP3B1).	[22]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of AP-3 complex subunit beta-1 (AP3B1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of AP-3 complex subunit beta-1 (AP3B1).	[23]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of AP-3 complex subunit beta-1 (AP3B1).	[24]

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] Several adaptor proteins promote intracellular localisation of the transporter MRP4/ABCC4 in platelets and haematopoietic cells.Thromb Haemost. 2017 Jan 5;117(1):105-115. doi: 10.1160/TH16-01-0045. Epub 2016 Oct 20.
• [3] Ocular Findings in Patients with the Hermansky-Pudlak Syndrome (Types 1 and 3).Ophthalmic Genet. 2016;37(1):89-94. doi: 10.3109/13816810.2014.907920. Epub 2014 Apr 28.
• [4] Effect of preoperative detrusor underactivity on long-term surgical outcomes of photovaporization and holmium laser enucleation in men with benign prostatic hyperplasia: a lesson from 5-year serial follow-up data.BJU Int. 2019 May;123(5A):E34-E42. doi: 10.1111/bju.14661. Epub 2019 Jan 27.
• [5] Mitochondria-targeted delivery of doxorubicin to enhance antitumor activity with HER-2 peptide-mediated multifunctional pH-sensitive DQAsomes.Int J Nanomedicine. 2018 Jul 18;13:4209-4226. doi: 10.2147/IJN.S163858. eCollection 2018.
• [6] The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2.Blood. 2013 Apr 11;121(15):2943-51. doi: 10.1182/blood-2012-10-463166. Epub 2013 Feb 12.
• [7] Novel AP3B1 compound heterozygous mutations in a Japanese patient with Hermansky-Pudlak syndrome type 2.J Dermatol. 2020 Feb;47(2):185-189. doi: 10.1111/1346-8138.15177. Epub 2019 Dec 9.
• [8] Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS).Hered Cancer Clin Pract. 2017 Nov 29;15:22. doi: 10.1186/s13053-017-0082-9. eCollection 2017.
• [9] Mutational data integration in gene-oriented files of the Hermansky-Pudlak Syndrome database.Hum Mutat. 2006 May;27(5):402-7. doi: 10.1002/humu.20309.
• [10] Different functions of biogenesis of lysosomal organelles complex 3 subunit 1 (Hps1) and adaptor-related protein complex 3, beta 1 subunit (Ap3b1) genes on spermatogenesis and male fertility.Reprod Fertil Dev. 2019 Apr;31(5):972-982. doi: 10.1071/RD18339.
• [11] Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019 Feb;51(2):230-236.
• [12] Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood.Orphanet J Rare Dis. 2018 Mar 27;13(1):42. doi: 10.1186/s13023-018-0780-z.
• [13] Characterizing renal involvement in Hermansky-Pudlak Syndrome in a zebrafish model.Sci Rep. 2019 Nov 27;9(1):17718. doi: 10.1038/s41598-019-54058-5.
• [14] Pulmonary Fibrosis in Hermansky-Pudlak Syndrome.Ann Am Thorac Soc. 2016 Oct;13(10):1839-1846. doi: 10.1513/AnnalsATS.201603-186FR.
• [15] Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.J Am Soc Nephrol. 2000 Aug;11(8):1449-1459. doi: 10.1681/ASN.V1181449.
• [16] Nontuberculous Mycobacterium infection complicated with Haemophagocytic syndrome: a case report and literature review.BMC Infect Dis. 2019 May 9;19(1):399. doi: 10.1186/s12879-019-4061-9.
• [17] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [18] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [21] 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.
• [22] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.