Details of Drug Off-Target (DOT)

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

• DOT Name: Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3)
• Synonyms: BLOC-1 subunit 3
• Gene Name: BLOC1S3
• Related Disease:
  Alzheimer disease
  Hermansky-Pudlak syndrome
  Hermansky-Pudlak syndrome 8
  Polycystic ovarian syndrome
  Prion disease
  Schizophrenia
• UniProt ID: BL1S3_HUMAN
• Pfam ID: PF15753
• Sequence:
  MASQGRRRRPLRRPETVVPGEATETDSERSASSSEEEELYLGPSGPTRGRPTGLRVAGEA
  AETDSEPEPEPEPTAAPRDLPPLVVQRESAEEAWGTEEAPAPAPARSLLQLRLAESQARL
  DHDVAAAVSGVYRRAGRDVAALASRLAAAQAAGLAAAHSVRLARGDLCALAERLDIVAGC
  RLLPDIRGVPGTEPEKDPGPRA
• Function: Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals. The BLOC-1 complex, in association with SNARE proteins, is also proposed to be involved in neurite extension. Plays a role in intracellular vesicle trafficking.
• Reactome Pathway: Golgi Associated Vesicle Biogenesis (R-HSA-432722)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Hermansky-Pudlak syndrome	DISCY0HQ	Strong	Genetic Variation	[2]
Hermansky-Pudlak syndrome 8	DIST2J91	Strong	Autosomal recessive	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[4]
Prion disease	DISOUMB0	Strong	Genetic Variation	[5]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[6]

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 Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[14]

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 decreases the methylation of Biogenesis of lysosome-related organelles complex 1 subunit 3 (BLOC1S3).	[12]

References

• [1] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [2] A BLOC-1 mutation screen reveals a novel BLOC1S3 mutation in Hermansky-Pudlak Syndrome type 8.Pigment Cell Melanoma Res. 2012 Sep;25(5):584-91. doi: 10.1111/j.1755-148X.2012.01029.x. Epub 2012 Aug 2.
• [3] A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8). Am J Hum Genet. 2006 Jan;78(1):160-6. doi: 10.1086/499338. Epub 2005 Nov 28.
• [4] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [5] Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.Hum Mol Genet. 2012 Apr 15;21(8):1897-906. doi: 10.1093/hmg/ddr607. Epub 2011 Dec 30.
• [6] An association study of the Hermansky-Pudlak syndrome type 4 gene in schizophrenic patients.Psychiatr Genet. 2013 Aug;23(4):163-73. doi: 10.1097/YPG.0b013e32836130a9.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.