Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDPS6AV)

• DOT Name: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A)
• Synonyms: Oligosaccharyl transferase subunit STT3A; STT3-A; EC 2.4.99.18; B5; Integral membrane protein 1; Transmembrane protein TMC
• Gene Name: STT3A
• Related Disease:
  African trypanosomiasis
  Anthrax
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Cervical cancer
  Cervical carcinoma
  Congenital disorder of glycosylation
  Congenital disorder of glycosylation, type Iw, autosomal dominant
  Epidermodysplasia verruciformis
  Herpes simplex infection
  IgA nephropathy
  Major depressive disorder
  Skin cancer
  STT3A-congenital disorder of glycosylation
  Thyroid gland follicular carcinoma
  Colon cancer
  Colon carcinoma
  Cutaneous squamous cell carcinoma
  Intellectual disability
  Schizophrenia
• UniProt ID: STT3A_HUMAN
• PDB ID: 6S7O; 8B6L
• EC Number: 2.4.99.18
• Pfam ID: PF02516 ; PF21436
• Sequence:
  MTKFGFLRLSYEKQDTLLKLLILSMAAVLSFSTRLFAVLRFESVIHEFDPYFNYRTTRFL
  AEEGFYKFHNWFDDRAWYPLGRIIGGTIYPGLMITSAAIYHVLHFFHITIDIRNVCVFLA
  PLFSSFTTIVTYHLTKELKDAGAGLLAAAMIAVVPGYISRSVAGSYDNEGIAIFCMLLTY
  YMWIKAVKTGSICWAAKCALAYFYMVSSWGGYVFLINLIPLHVLVLMLTGRFSHRIYVAY
  CTVYCLGTILSMQISFVGFQPVLSSEHMAAFGVFGLCQIHAFVDYLRSKLNPQQFEVLFR
  SVISLVGFVLLTVGALLMLTGKISPWTGRFYSLLDPSYAKNNIPIIASVSEHQPTTWSSY
  YFDLQLLVFMFPVGLYYCFSNLSDARIFIIMYGVTSMYFSAVMVRLMLVLAPVMCILSGI
  GVSQVLSTYMKNLDISRPDKKSKKQQDSTYPIKNEVASGMILVMAFFLITYTFHSTWVTS
  EAYSSPSIVLSARGGDGSRIIFDDFREAYYWLRHNTPEDAKVMSWWDYGYQITAMANRTI
  LVDNNTWNNTHISRVGQAMASTEEKAYEIMRELDVSYVLVIFGGLTGYSSDDINKFLWMV
  RIGGSTDTGKHIKENDYYTPTGEFRVDREGSPVLLNCLMYKMCYYRFGQVYTEAKRPPGF
  DRVRNAEIGNKDFELDVLEEAYTTEHWLVRIYKVKDLDNRGLSRT
• Function: Catalytic 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. This subunit contains the active site and the acceptor peptide and donor lipid-linked oligosaccharide (LLO) binding pockets. STT3A is present in the majority of OST complexes and mediates cotranslational N-glycosylation of most sites on target proteins, while STT3B-containing complexes are required for efficient post-translational glycosylation and mediate glycosylation of sites that have been skipped by STT3A.
• Tissue Specificity: Expressed at high levels in placenta, liver, muscle and pancreas, and at very low levels in brain, lung and kidney. Expressed in skin fibroblasts (at protein level).
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Maturation of spike protein (R-HSA-9694548)
  Asparagine N-linked glycosylation (R-HSA-446203)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
African trypanosomiasis	DISBIXK4	Strong	Biomarker	[1]
Anthrax	DISFPT78	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[5]
Congenital disorder of glycosylation, type Iw, autosomal dominant	DISGA722	Strong	Autosomal dominant	[6]
Epidermodysplasia verruciformis	DIS54WBS	Strong	Biomarker	[7]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[8]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[9]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[3]
Skin cancer	DISTM18U	Strong	Genetic Variation	[10]
STT3A-congenital disorder of glycosylation	DIS1SOPV	Strong	Autosomal recessive	[11]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Biomarker	[12]
Colon cancer	DISVC52G	moderate	Altered Expression	[13]
Colon carcinoma	DISJYKUO	moderate	Altered Expression	[13]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[14]
Intellectual disability	DISMBNXP	Limited	Biomarker	[11]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[15]

12 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 STT3A (STT3A).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[20]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[21]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[22]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[25]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit STT3A (STT3A).	[26]

References

• [1] 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.
• [2] Trimethyl Chitosan Nanoparticles Encapsulated Protective Antigen Protects the Mice Against Anthrax.Front Immunol. 2018 Mar 20;9:562. doi: 10.3389/fimmu.2018.00562. eCollection 2018.
• [3] Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.Lancet. 2013 Apr 20;381(9875):1371-1379. doi: 10.1016/S0140-6736(12)62129-1. Epub 2013 Feb 28.
• [4] TMC-SNPdb: an Indian germline variant database derived from whole exome sequences.Database (Oxford). 2016 Jul 9;2016:baw104. doi: 10.1093/database/baw104. Print 2016.
• [5] Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation Caused by Mutations in STT3A.J Child Neurol. 2017 May;32(6):560-565. doi: 10.1177/0883073817696816. Epub 2017 Mar 16.
• [6] Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings. Am J Hum Genet. 2021 Nov 4;108(11):2130-2144. doi: 10.1016/j.ajhg.2021.09.012. Epub 2021 Oct 14.
• [7] Development of a highly sensitive real-time one step RT-PCR combined complementary locked primer technology and conjugated minor groove binder probe.Virol J. 2011 Jun 29;8:330. doi: 10.1186/1743-422X-8-330.
• [8] Targeting STT3A-oligosaccharyltransferase with NGI-1 causes herpes simplex virus 1 dysfunction.FASEB J. 2019 Jun;33(6):6801-6812. doi: 10.1096/fj.201802044RR. Epub 2019 Feb 27.
• [9] A proliferation-inducing ligand (APRIL) induced hyper-production of IgA from tonsillar mononuclear cells in patients with IgA nephropathy.Cell Immunol. 2019 Jul;341:103925. doi: 10.1016/j.cellimm.2019.103925. Epub 2019 May 8.
• [10] Characterization of the transmembrane channel-like (TMC) gene family: functional clues from hearing loss and epidermodysplasia verruciformis.Genomics. 2003 Sep;82(3):300-8. doi: 10.1016/s0888-7543(03)00154-x.
• [11] Mutations in STT3A and STT3B cause two congenital disorders of glycosylation. Hum Mol Genet. 2013 Nov 15;22(22):4638-45. doi: 10.1093/hmg/ddt312. Epub 2013 Jul 10.
• [12] A preoperative diagnostic test that distinguishes benign from malignant thyroid carcinoma based on gene expression.J Clin Invest. 2004 Apr;113(8):1234-42. doi: 10.1172/JCI19617.
• [13] RETRACTED: KYA1797K down-regulates PD-L1 in colon cancer stem cells to block immune evasion by suppressing the -catenin/STT3 signaling pathway.Int Immunopharmacol. 2020 Jan;78:106003. doi: 10.1016/j.intimp.2019.106003. Epub 2019 Dec 5.
• [14] Risk of Cutaneous Squamous Cell Carcinoma Development in Renal Transplant Recipients Is Independent of TMC/EVER Alterations.Dermatology. 2015;231(3):245-52. doi: 10.1159/000435910. Epub 2015 Jul 28.
• [15] Evidence for schizophrenia susceptibility alleles in the Indian population: An association of neurodevelopmental genes in case-control and familial samples.Schizophr Res. 2015 Mar;162(1-3):112-7. doi: 10.1016/j.schres.2014.12.031. Epub 2015 Jan 9.
• [16] 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.
• [17] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [23] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [26] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.