Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0JZOMY)

• DOT Name: GTP-binding protein SAR1b (SAR1B)
• Synonyms: GTP-binding protein B; GTBPB
• Gene Name: SAR1B
• Related Disease:
  Abetalipoproteinemia
  Alzheimer disease
  Chylomicron retention disease
  Colorectal carcinoma
  Cone-rod dystrophy 2
  Dementia
  Hypobetalipoproteinemia
  Malabsorption syndrome
  Chronic diarrhoea
  Chronic obstructive pulmonary disease
• UniProt ID: SAR1B_HUMAN
• PDB ID: 8E0A; 8E0B; 8E0C; 8E0D
• Pfam ID: PF00025
• Sequence:
  MSFIFDWIYSGFSSVLQFLGLYKKTGKLVFLGLDNAGKTTLLHMLKDDRLGQHVPTLHPT
  SEELTIAGMTFTTFDLGGHVQARRVWKNYLPAINGIVFLVDCADHERLLESKEELDSLMT
  DETIANVPILILGNKIDRPEAISEERLREMFGLYGQTTGKGSISLKELNARPLEVFMCSV
  LKRQGYGEGFRWMAQYID
• Function: GTP-binding protein involved in transport from the endoplasmic reticulum to the Golgi apparatus. Activated by the guanine nucleotide exchange factor PREB. Involved in the selection of the protein cargo and the assembly of the COPII coat complex. Synergizes with the cargo receptor SURF4 to mediate the export of lipoproteins from the endoplasmic reticulum, thereby regulating lipoprotein delivery and the maintenance of lipid homeostasis.
• Tissue Specificity: Expressed in many tissues including small intestine, liver, muscle and brain.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Legionellosis (hsa05134)
• Reactome Pathway:
  COPII-mediated vesicle transport (R-HSA-204005)
  MHC class II antigen presentation (R-HSA-2132295)
  Cargo concentration in the ER (R-HSA-5694530)
  Chylomicron assembly (R-HSA-8963888)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen Presentation (R-HSA-983170)
  Regulation of cholesterol biosynthesis by SREBP (SREBF) (R-HSA-1655829)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abetalipoproteinemia	DISMSS7T	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Chylomicron retention disease	DISOUTV5	Strong	Autosomal recessive	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Cone-rod dystrophy 2	DISX2RWY	Strong	Genetic Variation	[5]
Dementia	DISXL1WY	Strong	Genetic Variation	[2]
Hypobetalipoproteinemia	DIS0TPI3	Strong	Genetic Variation	[6]
Malabsorption syndrome	DISGMUVS	Strong	Genetic Variation	[7]
Chronic diarrhoea	DISH3PX3	Limited	Biomarker	[8]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of GTP-binding protein SAR1b (SAR1B).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GTP-binding protein SAR1b (SAR1B).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of GTP-binding protein SAR1b (SAR1B).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTP-binding protein SAR1b (SAR1B).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of GTP-binding protein SAR1b (SAR1B).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of GTP-binding protein SAR1b (SAR1B).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of GTP-binding protein SAR1b (SAR1B).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of GTP-binding protein SAR1b (SAR1B).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of GTP-binding protein SAR1b (SAR1B).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of GTP-binding protein SAR1b (SAR1B).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of GTP-binding protein SAR1b (SAR1B).	[20]

References

• [1] Update on the molecular biology of dyslipidemias.Clin Chim Acta. 2016 Feb 15;454:143-85. doi: 10.1016/j.cca.2015.10.033. Epub 2015 Nov 4.
• [2] Genetic polymorphisms of lipid metabolism gene SAR1 homolog B and the risk of Alzheimer's disease and vascular dementia.J Formos Med Assoc. 2016 Jan;115(1):38-44. doi: 10.1016/j.jfma.2015.01.008. Epub 2015 Feb 19.
• [3] PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019 Nov;51(11):1560-1565. doi: 10.1038/s41588-019-0528-2.
• [4] Targeted Quantitative Proteomic Approach for Probing Altered Protein Expression of Small GTPases Associated with Colorectal Cancer Metastasis.Anal Chem. 2019 May 7;91(9):6233-6241. doi: 10.1021/acs.analchem.9b00938. Epub 2019 Apr 12.
• [5] 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.
• [6] Novel mutations of SAR1B gene in four children with chylomicron retention disease.J Clin Lipidol. 2019 Jul-Aug;13(4):554-562. doi: 10.1016/j.jacl.2019.05.013. Epub 2019 May 30.
• [7] Animal model of Sar1b deficiency presents lipid absorption deficits similar to Anderson disease.J Mol Med (Berl). 2015 Feb;93(2):165-76. doi: 10.1007/s00109-014-1247-x. Epub 2015 Jan 7.
• [8] Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein.Mol Genet Metab. 2008 Jan;93(1):74-84. doi: 10.1016/j.ymgme.2007.08.120. Epub 2007 Oct 22.
• [9] Breathing Out Completely Before Inhalation: The Most Problematic Step in Application Technique in Patients With Non-Mild Chronic Obstructive Pulmonary Disease.Front Pharmacol. 2019 Mar 12;10:241. doi: 10.3389/fphar.2019.00241. eCollection 2019.
• [10] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [13] 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.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] 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.
• [16] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.