Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEG4KU9)

• DOT Name: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1)
• Synonyms: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase 67 kDa subunit; Ribophorin I; RPN-I; Ribophorin-1
• Gene Name: RPN1
• Related Disease:
  Chronic renal failure
  Burkitt lymphoma
  leukaemia
  Leukemia
  Acute myelogenous leukaemia
  Coronary atherosclerosis
  Coronary heart disease
• UniProt ID: RPN1_HUMAN
• PDB ID: 6S7O; 6S7T; 8B6L
• Pfam ID: PF04597
• Sequence:
  MEAPAAGLFLLLLLGTWAPAPGSASSEAPPLINEDVKRTVDLSSHLAKVTAEVVLAHLGG
  GSTSRATSFLLALEPELEARLAHLGVQVKGEDEEENNLEVRETKIKGKSGRFFTVKLPVA
  LDPGAKISVIVETVYTHVLHPYPTQITQSEKQFVVFEGNHYFYSPYPTKTQTMRVKLASR
  NVESYTKLGNPTRSEDLLDYGPFRDVPAYSQDTFKVHYENNSPFLTITSMTRVIEVSHWG
  NIAVEENVDLKHTGAVLKGPFSRYDYQRQPDSGISSIRSFKTILPAAAQDVYYRDEIGNV
  STSHLLILDDSVEMEIRPRFPLFGGWKTHYIVGYNLPSYEYLYNLGDQYALKMRFVDHVF
  DEQVIDSLTVKIILPEGAKNIEIDSPYEISRAPDELHYTYLDTFGRPVIVAYKKNLVEQH
  IQDIVVHYTFNKVLMLQEPLLVVAAFYILFFTVIIYVRLDFSITKDPAAEARMKVACITE
  QVLTLVNKRIGLYRHFDETVNRYKQSRDISTLNSGKKSLETEHKALTSEIALLQSRLKTE
  GSDLCDRVSEMQKLDAQVKELVLKSAVEAERLVAGKLKKDTYIENEKLISGKRQELVTKI
  DHILDAL
• 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.
• Tissue Specificity: Expressed in all tissues tested.
• 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)
  Maturation of spike protein (R-HSA-9694548)
  SRP-dependent cotranslational protein targeting to membrane (R-HSA-1799339)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[2]
leukaemia	DISS7D1V	Strong	Genetic Variation	[3]
Leukemia	DISNAKFL	Strong	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[4]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[5]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[5]

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 Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[11]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[8]

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 increases the methylation of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit 1 (RPN1).	[14]

References

• [1] Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.Front Genet. 2019 May 24;10:494. doi: 10.3389/fgene.2019.00494. eCollection 2019.
• [2] Brassinosteroid reduces ABA accumulation leading to the inhibition of ABA-induced stomatal closure.Biochem Biophys Res Commun. 2018 Sep 26;504(1):143-148. doi: 10.1016/j.bbrc.2018.08.146. Epub 2018 Aug 29.
• [3] Breakpoints at 1p36.3 in three MDS/AML(M4) patients with t(1;3)(p36;q21) occur in the first intron and in the 5' region of MEL1.Genes Chromosomes Cancer. 2003 Mar;36(3):313-6. doi: 10.1002/gcc.10176.
• [4] Development of a dual-color, double fusion FISH assay to detect RPN1/EVI1 gene fusion associated with inv(3), t(3;3), and ins(3;3) in patients with myelodysplasia and acute myeloid leukemia.Am J Hematol. 2010 Aug;85(8):569-74. doi: 10.1002/ajh.21746.
• [5] Genetic variation associated with circulating monocyte count in the eMERGE Network.Hum Mol Genet. 2013 May 15;22(10):2119-27. doi: 10.1093/hmg/ddt010. Epub 2013 Jan 12.
• [6] 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.
• [7] 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.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.