Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDC90IS)

• DOT Name: GMP synthase (GMPS)
• Synonyms: EC 6.3.5.2; GMP synthetase; Glutamine amidotransferase
• Gene Name: GMPS
• UniProt ID: GUAA_HUMAN
• PDB ID: 2VPI; 2VXO
• EC Number: 6.3.5.2
• Pfam ID: PF00117 ; PF00958 ; PF02540
• Sequence:
  MALCNGDSKLENAGGDLKDGHHHYEGAVVILDAGAQYGKVIDRRVRELFVQSEIFPLETP
  AFAIKEQGFRAIIISGGPNSVYAEDAPWFDPAIFTIGKPVLGICYGMQMMNKVFGGTVHK
  KSVREDGVFNISVDNTCSLFRGLQKEEVVLLTHGDSVDKVADGFKVVARSGNIVAGIANE
  SKKLYGAQFHPEVGLTENGKVILKNFLYDIAGCSGTFTVQNRELECIREIKERVGTSKVL
  VLLSGGVDSTVCTALLNRALNQEQVIAVHIDNGFMRKRESQSVEEALKKLGIQVKVINAA
  HSFYNGTTTLPISDEDRTPRKRISKTLNMTTSPEEKRKIIGDTFVKIANEVIGEMNLKPE
  EVFLAQGTLRPDLIESASLVASGKAELIKTHHNDTELIRKLREEGKVIEPLKDFHKDEVR
  ILGRELGLPEELVSRHPFPGPGLAIRVICAEEPYICKDFPETNNILKIVADFSASVKKPH
  TLLQRVKACTTEEDQEKLMQITSLHSLNAFLLPIKTVGVQGDCRSYSYVCGISSKDEPDW
  ESLIFLARLIPRMCHNVNRVVYIFGPPVKEPPTDVTPTFLTTGVLSTLRQADFEAHNILR
  ESGYAGKISQMPVILTPLHFDRDPLQKQPSCQRSVVIRTFITSDFMTGIPATPGNEIPVE
  VVLKMVTEIKKIPGISRIMYDLTSKPPGTTEWE
• Function: Catalyzes the conversion of xanthine monophosphate (XMP) to GMP in the presence of glutamine and ATP through an adenyl-XMP intermediate.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Azathioprine ADME (R-HSA-9748787)
  Purine ribonucleoside monophosphate biosynthesis (R-HSA-73817)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of GMP synthase (GMPS).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GMP synthase (GMPS).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GMP synthase (GMPS).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of GMP synthase (GMPS).	[4]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of GMP synthase (GMPS).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of GMP synthase (GMPS).	[9]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of GMP synthase (GMPS).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of GMP synthase (GMPS).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of GMP synthase (GMPS).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of GMP synthase (GMPS).	[8]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [5] 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.
• [6] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [7] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [8] 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.
• [9] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.