Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE1V2P2)

• DOT Name: Tumor suppressor candidate 3
• Synonyms: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit TUSC3; Oligosaccharyl transferase subunit TUSC3; Magnesium uptake/transporter TUSC3; Protein N33
• Gene Name: TUSC3
• Related Disease:
  Intellectual disability
  Intellectual disability, autosomal recessive 7
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: TUSC3_HUMAN
• PDB ID: 4M8G; 4M90; 4M91; 4M92
• Pfam ID: PF04756
• Sequence:
  MGARGAPSRRRQAGRRLRYLPTGSFPFLLLLLLLCIQLGGGQKKKENLLAEKVEQLMEWS
  SRRSIFRMNGDKFRKFIKAPPRNYSMIVMFTALQPQRQCSVCRQANEEYQILANSWRYSS
  AFCNKLFFSMVDYDEGTDVFQQLNMNSAPTFMHFPPKGRPKRADTFDLQRIGFAAEQLAK
  WIADRTDVHIRVFRPPNYSGTIALALLVSLVGGLLYLRRNNLEFIYNKTGWAMVSLCIVF
  AMTSGQMWNHIRGPPYAHKNPHNGQVSYIHGSSQAQFVAESHIILVLNAAITMGMVLLNE
  AATSKGDVGKRRIICLVGLGLVVFFFSFLLSIFRSKYHGYPYSDLDFE
• Function: Acts as accessory component of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains. Involved in N-glycosylation of STT3B-dependent substrates. Specifically required for the glycosylation of a subset of acceptor sites that are near cysteine residues; in this function seems to act redundantly with MAGT1. In its oxidized form proposed to form transient mixed disulfides with a glycoprotein substrate to facilitate access of STT3B to the unmodified acceptor site. Has also oxidoreductase-independent functions in the STT3B-containing OST complex possibly involving substrate recognition; Magnesium transporter.
• Tissue Specificity: Expressed in most non-lymphoid cells and tissues examined, including prostate, lung, liver, colon, heart, kidney and pancreas.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Miscellaneous transport and binding events (R-HSA-5223345)
  Maturation of spike protein (R-HSA-9694548)
  Asparagine N-linked glycosylation (R-HSA-446203)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Autosomal recessive	[1]
Intellectual disability, autosomal recessive 7	DISVEC36	Definitive	Autosomal recessive	[2]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[3]

12 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 Tumor suppressor candidate 3.	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tumor suppressor candidate 3.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tumor suppressor candidate 3.	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tumor suppressor candidate 3.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tumor suppressor candidate 3.	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tumor suppressor candidate 3.	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Tumor suppressor candidate 3.	[11]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Tumor suppressor candidate 3.	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tumor suppressor candidate 3.	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Tumor suppressor candidate 3.	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tumor suppressor candidate 3.	[15]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Tumor suppressor candidate 3.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tumor suppressor candidate 3.	[9]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Oligosaccharyltransferase-subunit mutations in nonsyndromic mental retardation. Am J Hum Genet. 2008 May;82(5):1150-7. doi: 10.1016/j.ajhg.2008.03.021. Epub 2008 May 1.
• [3] A novel nonsense mutation in TUSC3 is responsible for non-syndromic autosomal recessive mental retardation in a consanguineous Iranian family. Am J Med Genet A. 2011 Aug;155A(8):1976-80. doi: 10.1002/ajmg.a.34077. Epub 2011 Jul 7.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] 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.
• [12] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [15] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [16] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.