Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ33OQV)

• DOT Name: Oxysterol-binding protein-related protein 1 (OSBPL1A)
• Synonyms: ORP-1; OSBP-related protein 1
• Gene Name: OSBPL1A
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Colorectal adenoma
  Non-insulin dependent diabetes
  Osteoporosis
  Dementia
  Neuroblastoma
• UniProt ID: OSBL1_HUMAN
• PDB ID: 5ZM5; 5ZM6; 5ZM7; 6IYB; 6TQS
• Pfam ID: PF12796 ; PF01237
• Sequence:
  MNTEAEQQLLHHARNGNAEEVRQLLETMARNEVIADINCKGRSKSNLGWTPLHLACYFGH
  RQVVQDLLKAGAEVNVLNDMGDTPLHRAAFTGRKELVMLLLEYNADTTIVNGSGQTAKEV
  THAEEIRSMLEAVERTQQRKLEELLLAAAREGKTTELTALLNRPNPPDVNCSDQLGNTPL
  HCAAYRAHKQCALKLLRSGADPNLKNKNDQKPLDLAQGAEMKHILVGNKVIYKALKRYEG
  PLWKSSRFFGWRLFWVVLEHGVLSWYRKQPDAVHNIYRQGCKHLTQAVCTVKSTDSCLFF
  IKCFDDTIHGFRVPKNSLQQSREDWLEAIEEHSAYSTHYCSQDQLTDEEEEDTVSAADLK
  KSLEKAQSCQQRLDREISNFLKMIKECDMAKEMLPSFLQKVEVVSEASRETCVALTDCLN
  LFTKQEGVRNFKLEQEQEKNKILSEALETLATEHHELEQSLVKGSPPASILSEDEFYDAL
  SDSESERSLSRLEAVTARSFEEEGEHLGSRKHRMSEEKDCGGGDALSNGIKKHRTSLPSP
  MFSRNDFSIWSILRKCIGMELSKITMPVIFNEPLSFLQRLTEYMEHTYLIHKASSLSDPV
  ERMQCVAAFAVSAVASQWERTGKPFNPLLGETYELVRDDLGFRLISEQVSHHPPISAFHA
  EGLNNDFIFHGSIYPKLKFWGKSVEAEPKGTITLELLEHNEAYTWTNPTCCVHNIIVGKL
  WIEQYGNVEIINHKTGDKCVLNFKPCGLFGKELHKVEGYIQDKSKKKLCALYGKWTECLY
  SVDPATFDAYKKNDKKNTEEKKNSKQMSTSEELDEMPVPDSESVFIIPGSVLLWRIAPRP
  PNSAQMYNFTSFAMVLNEVDKDMESVIPKTDCRLRPDIRAMENGEIDQASEEKKRLEEKQ
  RAARKNRSKSEEDWKTRWFHQGPNPYNGAQDWIYSGSYWDRNYFNLPDIY
• Function: Binds phospholipids; exhibits strong binding to phosphatidic acid and weak binding to phosphatidylinositol 3-phosphate. Stabilizes GTP-bound RAB7A on late endosomes/lysosomes and alters functional properties of late endocytic compartments via its interaction with RAB7A. Binds 25-hydroxycholesterol and cholesterol.
• Reactome Pathway:
  MHC class II antigen presentation (R-HSA-2132295)
  Synthesis of bile acids and bile salts (R-HSA-192105)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[2]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[4]
Dementia	DISXL1WY	moderate	Genetic Variation	[5]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[13]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[18]

2 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 affects the methylation of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Oxysterol-binding protein-related protein 1 (OSBPL1A).	[17]

References

• [1] Tumor-specific usage of alternative transcription start sites in colorectal cancer identified by genome-wide exon array analysis.BMC Genomics. 2011 Oct 14;12:505. doi: 10.1186/1471-2164-12-505.
• [2] A single nucleotide polymorphism located in microRNA-499a causes loss of function resulting in increased expression of osbpl1a and reduced serum HDL level.Oncol Rep. 2017 Dec;38(6):3515-3521. doi: 10.3892/or.2017.6016. Epub 2017 Oct 9.
• [3] T2DM GWAS in the Lebanese population confirms the role of TCF7L2 and CDKAL1 in disease susceptibility.Sci Rep. 2014 Dec 8;4:7351. doi: 10.1038/srep07351.
• [4] An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.PLoS Genet. 2010 Jun 10;6(6):e1000977. doi: 10.1371/journal.pgen.1000977.
• [5] Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.PLoS Genet. 2014 Sep 4;10(9):e1004606. doi: 10.1371/journal.pgen.1004606. eCollection 2014 Sep.
• [6] Family of human oxysterol binding protein (OSBP) homologues. A novel member implicated in brain sterol metabolism.J Lipid Res. 1999 Dec;40(12):2204-11.
• [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] 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.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.