Details of Drug Off-Target (DOT)

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

• DOT Name: GTP-binding protein SAR1a (SAR1A)
• Synonyms: COPII-associated small GTPase
• Gene Name: SAR1A
• Related Disease:
  Cerebellar degeneration
  Cone-rod dystrophy 2
  Glioblastoma multiforme
  Chylomicron retention disease
  Dystonia
  Familial hyperinsulinism
  Neoplasm
  Osteoarthritis
  Rheumatoid arthritis
  Sickle-cell anaemia
  Spinocerebellar ataxia type 2
  Substance abuse
  Advanced cancer
  Cerebellar ataxia
  Systemic primary carnitine deficiency disease
• UniProt ID: SAR1A_HUMAN
• PDB ID: 2GAO; 8DZM; 8DZN; 8DZO; 8DZT; 8E0H
• Pfam ID: PF00025
• Sequence:
  MSFIFEWIYNGFSSVLQFLGLYKKSGKLVFLGLDNAGKTTLLHMLKDDRLGQHVPTLHPT
  SEELTIAGMTFTTFDLGGHEQARRVWKNYLPAINGIVFLVDCADHSRLVESKVELNALMT
  DETISNVPILILGNKIDRTDAISEEKLREIFGLYGQTTGKGNVTLKELNARPMEVFMCSV
  LKRQGYGEGFRWLSQYID
• Function: Involved in transport from the endoplasmic reticulum to the Golgi apparatus. Required to maintain SEC16A localization at discrete locations on the ER membrane perhaps by preventing its dissociation. SAR1A-GTP-dependent assembly of SEC16A on the ER membrane forms an organized scaffold defining endoplasmic reticulum exit sites (ERES).
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Legionellosis (hsa05134)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar degeneration	DISPBCM3	Definitive	Biomarker	[1]
Cone-rod dystrophy 2	DISX2RWY	Definitive	Genetic Variation	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[3]
Chylomicron retention disease	DISOUTV5	Strong	Altered Expression	[4]
Dystonia	DISJLFGW	Strong	Biomarker	[5]
Familial hyperinsulinism	DISHQKQE	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[8]
Sickle-cell anaemia	DIS5YNZB	Strong	Biomarker	[9]
Spinocerebellar ataxia type 2	DISF7WDI	Strong	Biomarker	[10]
Substance abuse	DIS327VW	Strong	Biomarker	[11]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[12]
Cerebellar ataxia	DIS9IRAV	Limited	Biomarker	[13]
Systemic primary carnitine deficiency disease	DIS9OPZ4	Limited	Biomarker	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	GTP-binding protein SAR1a (SAR1A) affects the response to substance of Topotecan.	[23]

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 GTP-binding protein SAR1a (SAR1A).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GTP-binding protein SAR1a (SAR1A).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GTP-binding protein SAR1a (SAR1A).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTP-binding protein SAR1a (SAR1A).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of GTP-binding protein SAR1a (SAR1A).	[18]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of GTP-binding protein SAR1a (SAR1A).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of GTP-binding protein SAR1a (SAR1A).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GTP-binding protein SAR1a (SAR1A).	[21]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of GTP-binding protein SAR1a (SAR1A).	[22]

References

• [1] Extensive cerebellar and thalamic degeneration in spinocerebellar ataxia type 10.Parkinsonism Relat Disord. 2019 Sep;66:182-188. doi: 10.1016/j.parkreldis.2019.08.011. Epub 2019 Aug 19.
• [2] Chylomicron retention disease: a long term study of two cohorts.Mol Genet Metab. 2009 Jun;97(2):136-42. doi: 10.1016/j.ymgme.2009.02.003. Epub 2009 Feb 20.
• [3] CYP17A1 Maintains the Survival of Glioblastomas by Regulating SAR1-Mediated Endoplasmic Reticulum Health and Redox Homeostasis.Cancers (Basel). 2019 Sep 16;11(9):1378. doi: 10.3390/cancers11091378.
• [4] Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease). Orphanet J Rare Dis. 2011 Jan 14;6:1. doi: 10.1186/1750-1172-6-1.
• [5] Dystonia and ataxia progression in spinocerebellar ataxias.Parkinsonism Relat Disord. 2017 Dec;45:75-80. doi: 10.1016/j.parkreldis.2017.10.007. Epub 2017 Oct 23.
• [6] Sar1-GTPase-dependent ER exit of KATP channels revealed by a mutation causing congenital hyperinsulinism.Hum Mol Genet. 2009 Jul 1;18(13):2400-13. doi: 10.1093/hmg/ddp179. Epub 2009 Apr 8.
• [7] Angiotensin II type 1 receptor and ACTH receptor expression in human adrenocortical neoplasms.Clin Endocrinol (Oxf). 2001 May;54(5):627-32. doi: 10.1046/j.1365-2265.2001.01253.x.
• [8] Constitutive upregulation of the transforming growth factor-beta pathway in rheumatoid arthritis synovial fibroblasts.Arthritis Res Ther. 2007;9(3):R59. doi: 10.1186/ar2217.
• [9] The Responsiveness of Triaxial Accelerometer Measurement of Gait Ataxia Is Higher than That of the Scale for the Assessment and Rating of Ataxia in the Early Stages of Spinocerebellar Degeneration.Cerebellum. 2019 Aug;18(4):721-730. doi: 10.1007/s12311-019-01025-5.
• [10] NESSCA Validation and Responsiveness of Several Rating Scales in Spinocerebellar Ataxia Type 2.Cerebellum. 2017 Aug;16(4):852-858. doi: 10.1007/s12311-017-0855-8.
• [11] Substance abuse-related admissions in a mixed Norwegian intensive care population.Acta Anaesthesiol Scand. 2020 Mar;64(3):329-337. doi: 10.1111/aas.13506. Epub 2019 Nov 29.
• [12] Cancer in the Solomon Islands.Cancer Epidemiol. 2017 Oct;50(Pt B):176-183. doi: 10.1016/j.canep.2017.04.016.
• [13] Paediatric motor phenotypes in early-onset ataxia, developmental coordination disorder, and central hypotonia.Dev Med Child Neurol. 2020 Jan;62(1):75-82. doi: 10.1111/dmcn.14355. Epub 2019 Sep 17.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [19] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [20] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [23] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.