Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT123376)

• DOT Name: Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1)
• Synonyms: BLOC-1 subunit 1; GCN5-like protein 1; Protein RT14
• Gene Name: BLOC1S1
• Related Disease:
  Schizophrenia
  Complex neurodevelopmental disorder
• UniProt ID: BL1S1_HUMAN
• Pfam ID: PF06320
• Sequence:
  MAPGSRGERSSFRSRRGPGVPSPQPDVTMLSRLLKEHQAKQNERKELQEKRRREAITAAT
  CLTEALVDHLNVGVAQAYMNQRKLDHEVKTLQVQAAQFAKQTGQWIGMVENFNQALKEIG
  DVENWARSIELDMRTIATALEYVYKGQLQSAPS
• 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. As part of the BORC complex may play a role in lysosomes movement and localization at the cell periphery. Associated with the cytosolic face of lysosomes, the BORC complex may recruit ARL8B and couple lysosomes to microtubule plus-end-directed kinesin motor ; May negatively regulate aerobic respiration through mitochondrial protein lysine-acetylation. May counteract the action of the deacetylase SIRT3 by acetylating and regulating proteins of the mitochondrial respiratory chain including ATP5F1A and NDUFA9.
• Reactome Pathway:
  Golgi Associated Vesicle Biogenesis (R-HSA-432722)
  Lysosome Vesicle Biogenesis (R-HSA-432720)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Biomarker	[1]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[7]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[9]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1).	[10]

References

• [1] Gene dosage in the dysbindin schizophrenia susceptibility network differentially affect synaptic function and plasticity.J Neurosci. 2015 Jan 7;35(1):325-38. doi: 10.1523/JNEUROSCI.3542-14.2015.
• [2] Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders. Genet Med. 2021 Aug;23(8):1551-1568. doi: 10.1038/s41436-021-01159-0. Epub 2021 Apr 19.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] 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.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [9] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [10] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.