Details of Drug Off-Target (DOT)

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

• DOT Name: Dihydropyrimidinase (DPYS)
• Synonyms: DHP; DHPase; EC 3.5.2.2; Dihydropyrimidine amidohydrolase; Hydantoinase
• Gene Name: DPYS
• Related Disease:
  Advanced cancer
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Diabetic kidney disease
  Dihydropyrimidinuria
  Fibrosarcoma
  Hepatocellular carcinoma
  Hypokalemic periodic paralysis
  Hypokalemic periodic paralysis, type 1
  Myopathy
  Neoplasm
  Neuroblastoma
  Non-insulin dependent diabetes
  Papillon-Lefevre disease
  Post-traumatic stress disorder
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Stargardt disease
  West syndrome
  Bone Paget disease
  Paget's disease
  Acute respiratory failure
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: DPYS_HUMAN
• PDB ID: 2VR2
• EC Number: 3.5.2.2
• Pfam ID: PF01979
• Sequence:
  MAAPSRLLIRGGRVVNDDFSEVADVLVEDGVVRALGHDLLPPGGAPAGLRVLDAAGKLVL
  PGGIDTHTHMQFPFMGSRSIDDFHQGTKAALSGGTTMIIDFAIPQKGGSLIEAFETWRSW
  ADPKVCCDYSLHVAVTWWSDQVKEEMKILVQDKGVNSFKMFMAYKDLYMVTDLELYEAFS
  RCKEIGAIAQVHAENGDLIAEGAKKMLALGITGPEGHELCRPEAVEAEATLRAITIASAV
  NCPLYIVHVMSKSAAKVIADARRDGKVVYGEPIAASLGTDGTHYWNKEWHHAAHHVMGPP
  LRPDPSTPDFLMNLLANDDLTTTGTDNCTFNTCQKALGKDDFTKIPNGVNGVEDRMSVIW
  EKGVHSGKMDENRFVAVTSTNAAKIFNLYPRKGRIAVGSDADIVIWDPKGTRTISAKTHH
  QAVNFNIFEGMVCHGVPLVTISRGKVVYEAGVFSVTAGDGKFIPRKPFAEYIYKRIKQRD
  RTCTPTPVERAPYKGEVATLKSRVTKEDATAGTRKQAHP
• Function: Catalyzes the second step of the reductive pyrimidine degradation, the reversible hydrolytic ring opening of dihydropyrimidines. Can catalyze the ring opening of 5,6-dihydrouracil to N-carbamyl-alanine and of 5,6-dihydrothymine to N-carbamyl-amino isobutyrate.
• Tissue Specificity: Liver and kidney.
• KEGG Pathway:
  Pyrimidine metabolism (hsa00240)
  beta-Alanine metabolism (hsa00410)
  Pantothe.te and CoA biosynthesis (hsa00770)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Pyrimidine catabolism (R-HSA-73621)
• BioCyc Pathway: MetaCyc:HS07460-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[5]
Dihydropyrimidinuria	DISHMZMZ	Strong	Autosomal recessive	[6]
Fibrosarcoma	DISWX7MU	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Hypokalemic periodic paralysis	DISVIXI1	Strong	Genetic Variation	[8]
Hypokalemic periodic paralysis, type 1	DIS5GF2M	Strong	Genetic Variation	[8]
Myopathy	DISOWG27	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[10]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[11]
Papillon-Lefevre disease	DIS3R7KX	Strong	Biomarker	[12]
Post-traumatic stress disorder	DISHL1EY	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Stargardt disease	DISPXOTO	Strong	Genetic Variation	[14]
West syndrome	DISLIAU9	Strong	Altered Expression	[15]
Bone Paget disease	DISIPS4V	moderate	Genetic Variation	[16]
Paget's disease	DISO3MC0	moderate	Genetic Variation	[16]
Acute respiratory failure	DIS5KQ5Y	Limited	Biomarker	[17]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[18]
Liver cancer	DISDE4BI	Limited	Biomarker	[18]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[19]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[19]

9 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 Dihydropyrimidinase (DPYS).	[20]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dihydropyrimidinase (DPYS).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dihydropyrimidinase (DPYS).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Dihydropyrimidinase (DPYS).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dihydropyrimidinase (DPYS).	[24]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Dihydropyrimidinase (DPYS).	[25]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Dihydropyrimidinase (DPYS).	[25]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Dihydropyrimidinase (DPYS).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Dihydropyrimidinase (DPYS).	[27]

2 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 increases the methylation of Dihydropyrimidinase (DPYS).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dihydropyrimidinase (DPYS).	[29]

References

• [1] 1,4-Dihydropyridine: A Dependable Heterocyclic Ring with the Promising and the Most Anticipable Therapeutic Effects.Mini Rev Med Chem. 2019;19(15):1219-1254. doi: 10.2174/1389557519666190425184749.
• [2] Microtubule and microtubule associated protein anomalies in psychiatric disease.Cytoskeleton (Hoboken). 2016 Oct;73(10):596-611. doi: 10.1002/cm.21300. Epub 2016 May 20.
• [3] Identification of novel tumor markers in prostate, colon and breast cancer by unbiased methylation profiling.PLoS One. 2008 Apr 30;3(4):e2079. doi: 10.1371/journal.pone.0002079.
• [4] Genetic polymorphisms of dihydropyrimidinase in a Japanese patient with capecitabine-induced toxicity.PLoS One. 2015 Apr 27;10(4):e0124818. doi: 10.1371/journal.pone.0124818. eCollection 2015.
• [5] Nondihydropyridine Calcium Channel Blockers for the Treatment of Proteinuria: A Review of the Literature.Ann Pharmacother. 2019 Oct;53(10):1050-1059. doi: 10.1177/1060028019843644. Epub 2019 Apr 9.
• [6] Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients. Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):639-48. doi: 10.1016/j.bbadis.2010.03.013. Epub 2010 Apr 1.
• [7] Contribution of Molecular Structure to Self-Assembling and Biological Properties of Bifunctional Lipid-Like 4-(N-Alkylpyridinium)-1,4-Dihydropyridines.Pharmaceutics. 2019 Mar 12;11(3):115. doi: 10.3390/pharmaceutics11030115.
• [8] A novel sodium channel mutation in a family with hypokalemic periodic paralysis.Neurology. 1999 Dec 10;53(9):1932-6. doi: 10.1212/wnl.53.9.1932.
• [9] Skeletal muscle DHP receptor mutations alter calcium currents in human hypokalaemic periodic paralysis myotubes.J Physiol. 1995 Mar 1;483 ( Pt 2)(Pt 2):299-306. doi: 10.1113/jphysiol.1995.sp020586.
• [10] Dihydropyrimidinase-like protein 3 expression is negatively regulated by MYCN and associated with clinical outcome in neuroblastoma.Cancer Sci. 2013 Dec;104(12):1586-92. doi: 10.1111/cas.12278. Epub 2013 Oct 21.
• [11] Health profile and medication adherence of diabetic patients in the Portuguese population.Prim Care Diabetes. 2019 Oct;13(5):446-451. doi: 10.1016/j.pcd.2019.02.004. Epub 2019 Feb 21.
• [12] Analysis of copy number variation in 8,842 Korean individuals reveals 39 genes associated with hepatic biomarkers AST and ALT.BMB Rep. 2010 Aug;43(8):547-53. doi: 10.5483/bmbrep.2010.43.8.547.
• [13] Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD.Psychoneuroendocrinology. 2019 Apr;102:95-104. doi: 10.1016/j.psyneuen.2018.11.027. Epub 2018 Nov 22.
• [14] Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease.J Biol Chem. 2009 Jul 24;284(30):20155-66. doi: 10.1074/jbc.M109.021345. Epub 2009 May 28.
• [15] Dihydropyrimidinase deficiency in four East Asian patients due to novel and rare DPYS mutations affecting protein structural integrity and catalytic activity.Mol Genet Metab. 2017 Dec;122(4):216-222. doi: 10.1016/j.ymgme.2017.10.003. Epub 2017 Oct 12.
• [16] Genome-wide association identifies three new susceptibility loci for Paget's disease of bone.Nat Genet. 2011 May 29;43(7):685-9. doi: 10.1038/ng.845.
• [17] Efficacy of direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP) in rapidly progressive interstitial pneumonias: results of a historical control study and a review of previous studies.Ther Adv Respir Dis. 2017 Jul;11(7):261-275. doi: 10.1177/1753465817708950. Epub 2017 May 30.
• [18] Novel 1,4-dihydropyridine induces apoptosis in human cancer cells through overexpression of Sirtuin1.Apoptosis. 2018 Oct;23(9-10):532-553. doi: 10.1007/s10495-018-1483-6.
• [19] Psychometric testing of the Norwegian Diabetes Health Profile (DHP-18) in patients with type 1 diabetes.BMJ Open Diabetes Res Care. 2018 Dec 6;6(1):e000541. doi: 10.1136/bmjdrc-2018-000541. eCollection 2018.
• [20] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [21] 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.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [24] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [25] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [26] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] 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.
• [29] 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.