Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT39PDMS)

• DOT Name: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST)
• Synonyms: DDOST 48 kDa subunit; Oligosaccharyl transferase 48 kDa subunit
• Gene Name: DDOST
• Related Disease:
  Bone osteosarcoma
  Chronic kidney disease
  DDOST-congenital disorder of glycosylation
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Nephropathy
  Osteosarcoma
  Retinopathy
  Type-1/2 diabetes
  African trypanosomiasis
  Congenital disorder of glycosylation
  Fatty liver disease
  Hepatitis C virus infection
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-alcoholic fatty liver disease
  Prostate cancer
  Prostate carcinoma
  Vascular disease
  Yellow fever virus infection
  Influenza
  Osteoporosis
  Periodontitis
• UniProt ID: OST48_HUMAN
• PDB ID: 6S7O; 6S7T; 8B6L
• Pfam ID: PF03345
• Sequence:
  MGYFRCARAGSFGRRRKMEPSTAARAWALFWLLLPLLGAVCASGPRTLVLLDNLNVRETH
  SLFFRSLKDRGFELTFKTADDPSLSLIKYGEFLYDNLIIFSPSVEDFGGNINVETISAFI
  DGGGSVLVAASSDIGDPLRELGSECGIEFDEEKTAVIDHHNYDISDLGQHTLIVADTENL
  LKAPTIVGKSSLNPILFRGVGMVADPDNPLVLDILTGSSTSYSFFPDKPITQYPHAVGKN
  TLLIAGLQARNNARVIFSGSLDFFSDSFFNSAVQKAAPGSQRYSQTGNYELAVALSRWVF
  KEEGVLRVGPVSHHRVGETAPPNAYTVTDLVEYSIVIQQLSNGKWVPFDGDDIQLEFVRI
  DPFVRTFLKKKGGKYSVQFKLPDVYGVFQFKVDYNRLGYTHLYSSTQVSVRPLQHTQYER
  FIPSAYPYYASAFSMMLGLFIFSIVFLHMKEKEKSD
• Function: Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation. N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity. Required for the assembly of both SST3A- and SS3B-containing OST complexes.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Asparagine N-linked glycosylation (R-HSA-446203)
  Neutrophil degranulation (R-HSA-6798695)
  Advanced glycosylation endproduct receptor signaling (R-HSA-879415)
  Maturation of spike protein (R-HSA-9694548)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Chronic kidney disease	DISW82R7	Definitive	Biomarker	[2]
DDOST-congenital disorder of glycosylation	DISYJU14	Definitive	Autosomal recessive	[3]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Definitive	Genetic Variation	[4]
Nephropathy	DISXWP4P	Definitive	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Retinopathy	DISB4B0F	Definitive	Altered Expression	[5]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[6]
African trypanosomiasis	DISBIXK4	Strong	Biomarker	[7]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[3]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Vascular disease	DISVS67S	Strong	Biomarker	[14]
Yellow fever virus infection	DISK0X5T	Strong	Biomarker	[15]
Influenza	DIS3PNU3	moderate	Biomarker	[16]
Osteoporosis	DISF2JE0	Limited	Biomarker	[17]
Periodontitis	DISI9JOI	Limited	Altered Expression	[18]

8 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 Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[24]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[25]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[24]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 48 kDa subunit (DDOST).	[28]

References

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• [3] DDOST mutations identified by whole-exome sequencing are implicated in congenital disorders of glycosylation. Am J Hum Genet. 2012 Feb 10;90(2):363-8. doi: 10.1016/j.ajhg.2011.12.024. Epub 2012 Feb 2.
• [4] Structure Based Substrate Specificity Analysis of Heparan Sulfate 6-O-Sulfotransferases.ACS Chem Biol. 2017 Jan 20;12(1):73-82. doi: 10.1021/acschembio.6b00841. Epub 2016 Nov 22.
• [5] Dietary advanced glycated end-products and medicines influence the expression of SIRT1 and DDOST in peripheral mononuclear cells from long-term type 1 diabetes patients.Diab Vasc Dis Res. 2018 Jan;15(1):81-89. doi: 10.1177/1479164117733918. Epub 2017 Oct 13.
• [6] Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion.Sci Rep. 2019 Sep 20;9(1):13664. doi: 10.1038/s41598-019-50221-0.
• [7] Single-subunit oligosaccharyltransferases of Trypanosoma brucei display different and predictable peptide acceptor specificities.J Biol Chem. 2017 Dec 8;292(49):20328-20341. doi: 10.1074/jbc.M117.810945. Epub 2017 Sep 19.
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• [11] Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas.Clin Cancer Res. 2011 Apr 1;17(7):1828-38. doi: 10.1158/1078-0432.CCR-10-2066. Epub 2011 Feb 16.
• [12] A targeted analysis reveals relevant shifts in the methylation and transcription of genes responsible for bile acid homeostasis and drug metabolism in non-alcoholic fatty liver disease. BMC Genomics. 2016 Jun 14;17:462.
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• [14] AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-delta: implications for vascular disease.Am J Physiol Cell Physiol. 2010 Mar;298(3):C624-34. doi: 10.1152/ajpcell.00463.2009. Epub 2009 Dec 2.
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• [16] Preliminary results on the uptake and biochemical response to water-exposure of Tamiflu (oseltamivir phosphate) in two marine bivalves.J Toxicol Environ Health A. 2019;82(2):75-85. doi: 10.1080/15287394.2018.1562393. Epub 2019 Jan 22.
• [17] Utility of Osteoporosis Self-Assessment Tool as a Screening Tool for Predicting Osteoporosis in Indian Men.J Clin Densitom. 2017 Apr-Jun;20(2):160-163. doi: 10.1016/j.jocd.2016.04.005. Epub 2016 May 17.
• [18] Soluble Forms of the Receptor for Advanced Glycation Endproducts (RAGE) in Periodontitis.Sci Rep. 2019 Jun 3;9(1):8170. doi: 10.1038/s41598-019-44608-2.
• [19] 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.
• [20] 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.
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• [22] 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.
• [23] Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells. Biochemistry. 2007 Aug 7;46(31):8920-32. doi: 10.1021/bi7000328. Epub 2007 Jul 14.
• [24] 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.
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