Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXSDU14)

• DOT Name: Transmembrane protein 258 (TMEM258)
• Synonyms: Dolichyl-diphosphooligosaccharide--protein glycosyltransferase subunit TMEM258; Oligosaccharyl transferase subunit TMEM258
• Gene Name: TMEM258
• Related Disease:
  Chronic kidney disease
  Chronic renal failure
  Colitis
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Nasal polyp
  Ankylosing spondylitis
  Asthma
  Crohn disease
  Lung cancer
  Psoriasis
  Sclerosing cholangitis
  Ulcerative colitis
• UniProt ID: TM258_HUMAN
• PDB ID: 6S7O; 6S7T; 8B6L
• Pfam ID: PF05251
• Sequence:
  MELEAMSRYTSPVNPAVFPHLTVVLLAIGMFFTAWFFVYEVTSTKYTRDIYKELLISLVA
  SLFMGFGVLFLLLWVGIYV
• 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. Involved in ER homeostasis in the colonic epithelium.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Protein processing in endoplasmic reticulum (hsa04141)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Colitis	DISAF7DD	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Genetic Variation	[3]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[3]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[4]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[3]
Nasal polyp	DISLP3XE	Strong	Genetic Variation	[5]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[6]
Asthma	DISW9QNS	Limited	Genetic Variation	[7]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[6]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[8]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[6]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[6]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[6]

6 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 Transmembrane protein 258 (TMEM258).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane protein 258 (TMEM258).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Transmembrane protein 258 (TMEM258).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transmembrane protein 258 (TMEM258).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Transmembrane protein 258 (TMEM258).	[13]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Transmembrane protein 258 (TMEM258).	[14]

References

• [1] Genome-Wide Association Studies of Metabolites in Patients with CKD Identify Multiple Loci and Illuminate Tubular Transport Mechanisms.J Am Soc Nephrol. 2018 May;29(5):1513-1524. doi: 10.1681/ASN.2017101099. Epub 2018 Mar 15.
• [2] TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation.Cell Rep. 2016 Dec 13;17(11):2955-2965. doi: 10.1016/j.celrep.2016.11.042.
• [3] Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.Gastroenterology. 2019 Apr;156(5):1455-1466. doi: 10.1053/j.gastro.2018.11.066. Epub 2018 Dec 6.
• [4] Discovery of common and rare genetic risk variants for colorectal cancer.Nat Genet. 2019 Jan;51(1):76-87. doi: 10.1038/s41588-018-0286-6. Epub 2018 Dec 3.
• [5] A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.Nat Genet. 2019 Feb;51(2):267-276. doi: 10.1038/s41588-018-0314-6. Epub 2019 Jan 14.
• [6] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [7] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [8] A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese.Nat Genet. 2011 Jul 3;43(8):792-6. doi: 10.1038/ng.875.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [12] 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.
• [13] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [14] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.