Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM79LML)

• DOT Name: Trimethylguanosine synthase (TGS1)
• Synonyms: EC 2.1.1.-; CLL-associated antigen KW-2; Cap-specific guanine-N2 methyltransferase; Hepatocellular carcinoma-associated antigen 137; Nuclear receptor coactivator 6-interacting protein; PRIP-interacting protein with methyltransferase motif; PIMT; PIPMT
• Gene Name: TGS1
• Related Disease:
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Leukopenia
  Parkinson disease
  Thrombocytopenia
  Tuberculosis
• UniProt ID: TGS1_HUMAN
• PDB ID: 3EGI; 3GDH
• EC Number: 2.1.1.-
• Pfam ID: PF09445
• Sequence:
  MCCEKWSRVAEMFLFIEEREDCKILCLCSRAFVEDRKLYNLGLKGYYIRDSGNNSGDQAT
  EEEEGGYSCGTAESHDSKGIGLDESELDSEAELMRSMGLPLQFGRITAHKDFEVSMNTRN
  KVKIKKKKHQKKYLDEIVQESWRKEYEEDDILASDDPSSIEQYENTRTYELQSKKDTETE
  NPPVENTLSPKLEITEKWEKYWNEYGGGLLWQSWQEKHPGQALSSEPWNFPDTKEEWEQH
  YSQLYWYYLEQFQYWEAQGWTFDASQSCDTDTYTSKTEADDKNDEKCMKVDLVSFPSSPI
  MVDNDSSGTSDKDHSEILDGISNIKLNSEEVTQSQLDSCTSHDGHQQLSEVSSKRECPAS
  GQSEPRNGGTNEESNSSGNTNTDPPAEDSQKSSGANTSKDRPHASGTDGDESEEDPPEHK
  PSKLKRSHELDIDENPASDFDDSGSLLGFKYGSGQKYGGIPNFSHRQVRYLEKNVKLKSK
  YLDMRRQIKMKNKHIFFTKESEKPFFKKSKILSKVEKFLTWVNKPMDEEASQESSSHDNV
  HDASTSSDSEEQDMSVKKGDDLLETNNPEPEKCQSVSSAGELETENYERDSLLATVPDEQ
  DCVTQEVPDSRQAETEAEVKKKKNKKKNKKVNGLPPEIAAVPELAKYWAQRYRLFSRFDD
  GIKLDREGWFSVTPEKIAEHIAGRVSQSFKCDVVVDAFCGVGGNTIQFALTGMRVIAIDI
  DPVKIALARNNAEVYGIADKIEFICGDFLLLASFLKADVVFLSPPWGGPDYATAETFDIR
  TMMSPDGFEIFRLSKKITNNIVYFLPRNADIDQVASLAGPGGQVEIEQNFLNNKLKTITA
  YFGDLIRRPASET
• Function: Catalyzes the 2 serial methylation steps for the conversion of the 7-monomethylguanosine (m(7)G) caps of snRNAs and snoRNAs to a 2,2,7-trimethylguanosine (m(2,2,7)G) cap structure. The enzyme is specific for guanine, and N7 methylation must precede N2 methylation. Hypermethylation of the m7G cap of U snRNAs leads to their concentration in nuclear foci, their colocalization with coilin and the formation of canonical Cajal bodies (CBs). Plays a role in transcriptional regulation.
• Tissue Specificity: Ubiquitously expressed. High expression in heart, skeletal muscle, kidney, liver and placenta.
• Reactome Pathway:
  BMAL1 (R-HSA-1368108)
  snRNP Assembly (R-HSA-191859)
  PPARA activates gene expression (R-HSA-1989781)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Regulation of lipid metabolism by PPARalpha (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  Heme signaling (R-HSA-9707616)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Leukopenia	DISJMBMM	Strong	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[3]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[2]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Trimethylguanosine synthase (TGS1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Trimethylguanosine synthase (TGS1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Trimethylguanosine synthase (TGS1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Trimethylguanosine synthase (TGS1).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Trimethylguanosine synthase (TGS1).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Trimethylguanosine synthase (TGS1).	[11]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Trimethylguanosine synthase (TGS1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Trimethylguanosine synthase (TGS1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Trimethylguanosine synthase (TGS1).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Trimethylguanosine synthase (TGS1).	[9]

References

• [1] PIMT/NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism.Int J Mol Sci. 2018 May 16;19(5):1485. doi: 10.3390/ijms19051485.
• [2] Clinical significance of lnc-AC145676.2.1-6 and lnc-TGS1-1 and their variants in western Chinese tuberculosis patients.Int J Infect Dis. 2019 Jul;84:8-14. doi: 10.1016/j.ijid.2019.04.018. Epub 2019 Apr 24.
• [3] Dopamine down-regulation of protein L-isoaspartyl methyltransferase is dependent on reactive oxygen species in SH-SY5Y cells. Neuroscience. 2014 May 16;267:263-76. doi: 10.1016/j.neuroscience.2014.03.001. Epub 2014 Mar 12.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [9] 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.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [12] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.