Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT59E0KX)

• DOT Name: mRNA-capping enzyme (RNGTT)
• Synonyms: HCAP1; HCE
• Gene Name: RNGTT
• Related Disease:
  Rabies
  Advanced cancer
  Alpha thalassemia
  Beta thalassemia
  Carcinoma of liver and intrahepatic biliary tract
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Early-onset anterior polar cataract
  Endometrium neoplasm
  Hepatocellular carcinoma
  High blood pressure
  Liver cancer
  Narcolepsy
  Neoplasm
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Stroke
• UniProt ID: MCE1_HUMAN
• PDB ID: 2C46; 3S24; 8P4A; 8P4B; 8P4C; 8P4D; 8P4E
• EC Number: 2.7.7.50; 3.6.1.74
• Pfam ID: PF00782 ; PF03919 ; PF01331
• Sequence:
  MAHNKIPPRWLNCPRRGQPVAGRFLPLKTMLGPRYDSQVAEENRFHPSMLSNYLKSLKVK
  MGLLVDLTNTSRFYDRNDIEKEGIKYIKLQCKGHGECPTTENTETFIRLCERFNERNPPE
  LIGVHCTHGFNRTGFLICAFLVEKMDWSIEAAVATFAQARPPGIYKGDYLKELFRRYGDI
  EEAPPPPLLPDWCFEDDEDEDEDEDGKKESEPGSSASFGKRRKERLKLGAIFLEGVTVKG
  VTQVTTQPKLGEVQQKCHQFCGWEGSGFPGAQPVSMDKQNIKLLDLKPYKVSWKADGTRY
  MMLIDGTNEVFMIDRDNSVFHVSNLEFPFRKDLRMHLSNTLLDGEMIIDRVNGQAVPRYL
  IYDIIKFNSQPVGDCDFNVRLQCIEREIISPRHEKMKTGLIDKTQEPFSVRNKPFFDICT
  SRKLLEGNFAKEVSHEMDGLIFQPTGKYKPGRCDDILKWKPPSLNSVDFRLKITRMGGEG
  LLPQNVGLLYVGGYERPFAQIKVTKELKQYDNKIIECKFENNSWVFMRQRTDKSFPNAYN
  TAMAVCNSISNPVTKEMLFEFIDRCTAASQGQKRKHHLDPDTELMPPPPPKRPRPLT
• Function: Bifunctional mRNA-capping enzyme exhibiting RNA 5'-triphosphate monophosphatase activity in the N-terminal part and mRNA guanylyltransferase activity in the C-terminal part. Catalyzes the first two steps of cap formation: by removing the gamma-phosphate from the 5'-triphosphate end of nascent mRNA to yield a diphosphate end, and by transferring the GMP moiety of GTP to the 5'-diphosphate terminus of RNA via a covalent enzyme-GMP reaction intermediate.
• Tissue Specificity: Isoform 1 and isoform 4 (at a lesser extent) are expressed in cerebrum, cerebellum, thyroid, lung, heart, liver, kidney, spleen, large intestine, testis, skin and muscle.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  mRNA Capping (R-HSA-72086)
  RNA Pol II CTD phosphorylation and interaction with CE (R-HSA-77075)
  RNA Pol II CTD phosphorylation and interaction with CE during HIV infection (R-HSA-167160)
• BioCyc Pathway: MetaCyc:HS03479-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rabies	DISSC4V5	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alpha thalassemia	DIS5XGK0	Strong	Genetic Variation	[3]
Beta thalassemia	DIS5RCQK	Strong	Genetic Variation	[3]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Genetic Variation	[4]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[4]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[4]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[4]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[4]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[4]
Early-onset anterior polar cataract	DISTOPIY	Strong	Biomarker	[5]
Endometrium neoplasm	DIS6OS2L	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[2]
High blood pressure	DISY2OHH	Strong	Altered Expression	[6]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Pneumonia	DIS8EF3M	Strong	Genetic Variation	[5]
Pneumonitis	DIS88E0K	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
Stroke	DISX6UHX	Limited	Biomarker	[9]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of mRNA-capping enzyme (RNGTT).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of mRNA-capping enzyme (RNGTT).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of mRNA-capping enzyme (RNGTT).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of mRNA-capping enzyme (RNGTT).	[13]
AT13387	DM2B9E0	Phase 1	AT13387 decreases the expression of mRNA-capping enzyme (RNGTT).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of mRNA-capping enzyme (RNGTT).	[16]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of mRNA-capping enzyme (RNGTT).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of mRNA-capping enzyme (RNGTT).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of mRNA-capping enzyme (RNGTT).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of mRNA-capping enzyme (RNGTT).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of mRNA-capping enzyme (RNGTT).	[14]

References

• [1] A dual-functional priming-capping loop of rhabdoviral RNA polymerases directs terminal de novo initiation and capping intermediate formation.Nucleic Acids Res. 2019 Jan 10;47(1):299-309. doi: 10.1093/nar/gky1058.
• [2] Two variants of the human hepatocellular carcinoma-associated HCAP1 gene and their effect on the growth of the human liver cancer cell line Hep3B.Genes Chromosomes Cancer. 2004 Jan;39(1):48-58. doi: 10.1002/gcc.10293.
• [3] The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians.Eur J Haematol. 2007 Nov;79(5):417-21. doi: 10.1111/j.1600-0609.2007.00958.x. Epub 2007 Sep 27.
• [4] Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1.Sci Rep. 2015 Dec 1;5:17369. doi: 10.1038/srep17369.
• [5] Rates of hospitalization for community-acquired pneumonia among US adults: A systematic review.Vaccine. 2020 Jan 22;38(4):741-751. doi: 10.1016/j.vaccine.2019.10.101. Epub 2019 Dec 13.
• [6] Inhibition of human liver carboxylesterase (hCE1) by organophosphate ester flame retardants and plasticizers: implications for pharmacotherapy. Toxicol Sci. 2019 Jul 3. pii: kfz149.
• [7] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [8] Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness.Oncotarget. 2017 Jul 18;8(29):47110-47120. doi: 10.18632/oncotarget.16943.
• [9] A multidirectional approach to risk assessment in patients with three-vessel coronary artery disease undergoing percutaneous intervention.J Cardiol. 2017 Apr;69(4):640-647. doi: 10.1016/j.jjcc.2016.06.006. Epub 2016 Jul 16.
• [10] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] RNA-binding proteins and heat-shock protein 90 are constituents of the cytoplasmic capping enzyme interactome. J Biol Chem. 2018 Oct 26;293(43):16596-16607. doi: 10.1074/jbc.RA118.004973. Epub 2018 Aug 30.
• [16] 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.
• [17] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [18] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.