Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM061UK)

• DOT Name: Uridine 5'-monophosphate synthase
• Synonyms: UMP synthase
• Gene Name: UMPS
• Related Disease: Orotic aciduria
• UniProt ID: UMPS_HUMAN
• PDB ID: 2EAW ; 2JGY ; 2P1F ; 2QCC ; 2QCD ; 2QCE ; 2QCF ; 2QCG ; 2QCH ; 2QCL ; 2QCM ; 2QCN ; 2V30 ; 2WNS ; 3BGG ; 3BGJ ; 3BK0 ; 3BVJ ; 3DBP ; 3EWU ; 3EWW ; 3EWX ; 3EWY ; 3EWZ ; 3EX1 ; 3EX2 ; 3EX3 ; 3EX4 ; 3EX6 ; 3G3D ; 3G3M ; 3L0K ; 3L0N ; 3MI2 ; 3MO7 ; 3MW7 ; 4HIB ; 4HKP ; 6YVK ; 6YVL ; 6YVM ; 6YVN ; 6YVO ; 6YWT ; 6YWU ; 6ZWY ; 6ZWZ ; 6ZX0 ; 6ZX1 ; 6ZX2 ; 6ZX3 ; 7AM9 ; 7ASQ ; 7OQF ; 7OQI ; 7OQK ; 7OQM ; 7OQN ; 7OTU ; 7OUZ ; 7OV0 ; 7Q1H
• EC Number: 2.4.2.10; 4.1.1.23
• Pfam ID: PF00215 ; PF00156
• Sequence:
  MAVARAALGPLVTGLYDVQAFKFGDFVLKSGLSSPIYIDLRGIVSRPRLLSQVADILFQT
  AQNAGISFDTVCGVPYTALPLATVICSTNQIPMLIRRKETKDYGTKRLVEGTINPGETCL
  IIEDVVTSGSSVLETVEVLQKEGLKVTDAIVLLDREQGGKDKLQAHGIRLHSVCTLSKML
  EILEQQKKVDAETVGRVKRFIQENVFVAANHNGSPLSIKEAPKELSFGARAELPRIHPVA
  SKLLRLMQKKETNLCLSADVSLARELLQLADALGPSICMLKTHVDILNDFTLDVMKELIT
  LAKCHEFLIFEDRKFADIGNTVKKQYEGGIFKIASWADLVNAHVVPGSGVVKGLQEVGLP
  LHRGCLLIAEMSSTGSLATGDYTRAAVRMAEEHSEFVVGFISGSRVSMKPEFLHLTPGVQ
  LEAGGDNLGQQYNSPQEVIGKRGSDIIIVGRGIISAADRLEAAEMYRKAAWEAYLSRLGV
• Function: Bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT), which converts orotate to orotidine-5'-monophosphate (OMP), and orotidine-5'-monophosphate decarboxylase (ODC), the terminal enzymatic reaction that decarboxylates OMP to uridine monophosphate (UMP).
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Pyrimidine biosynthesis (R-HSA-500753)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Orotic aciduria	DISUVPQG	Definitive	Autosomal recessive	[1]

17 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 Uridine 5'-monophosphate synthase.	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Uridine 5'-monophosphate synthase.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Uridine 5'-monophosphate synthase.	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Uridine 5'-monophosphate synthase.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Uridine 5'-monophosphate synthase.	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Uridine 5'-monophosphate synthase.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Uridine 5'-monophosphate synthase.	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Uridine 5'-monophosphate synthase.	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Uridine 5'-monophosphate synthase.	[11]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Uridine 5'-monophosphate synthase.	[6]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of Uridine 5'-monophosphate synthase.	[6]
Docetaxel	DMDI269	Approved	Docetaxel increases the expression of Uridine 5'-monophosphate synthase.	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Uridine 5'-monophosphate synthase.	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Uridine 5'-monophosphate synthase.	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Uridine 5'-monophosphate synthase.	[18]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Uridine 5'-monophosphate synthase.	[19]
Wogonin	DMGCF51	Investigative	Wogonin decreases the expression of Uridine 5'-monophosphate synthase.	[20]

2 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 Uridine 5'-monophosphate synthase.	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Uridine 5'-monophosphate synthase.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the response to substance of Uridine 5'-monophosphate synthase.	[12]
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Uridine 5'-monophosphate synthase.	[14]

References

• [1] Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. Am J Hum Genet. 1997 Mar;60(3):525-39.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Influence of chemotherapeutic agents and cytokines on the expression of 5-fluorouracil-associated enzymes in human colon cancer cell lines. J Gastroenterol. 2006 Feb;41(2):140-50.
• [7] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [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] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [12] Orotate phosphoribosyltransferase expression level in tumors is a potential determinant of the efficacy of 5-fluorouracil. Biochem Biophys Res Commun. 2007 Nov 9;363(1):216-22. doi: 10.1016/j.bbrc.2007.08.164. Epub 2007 Sep 6.
• [13] Synergistic effects of docetaxel and S-1 by modulating the expression of metabolic enzymes of 5-fluorouracil in human gastric cancer cell lines. Int J Cancer. 2006 Aug 15;119(4):783-91.
• [14] 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.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [20] Wogonin potentiates the antitumor effects of low dose 5-fluorouracil against gastric cancer through induction of apoptosis by down-regulation of NF-kappaB and regulation of its metabolism. Toxicol Lett. 2010 Sep 1;197(3):201-10.