Target Information

Target General Infomation
Target ID
T40954
Former ID
TTDS00056
Target Name
Xanthine dehydrogenase/oxidase
Gene Name
XDH
Synonyms
Xanthine oxidase; XDH
Target Type
Successful
Disease Cancer [ICD9: 140-229; ICD10: C00-C96]
Encephalopathy [ICD10: G93.4]
Gout [ICD9: 274.00274.1274.8274.9; ICD10: M10]
Hyperuricemia [ICD9: 790.6; ICD10: E79.0]
Hyperuricaemia in gout [ICD9: 274, 790.6; ICD10: E79.0, M10]
Heart failure [ICD9: 428; ICD10: I50]
Function
Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro).
BioChemical Class
Oxidoreductases acting on CH or CH(2) groups
Target Validation
T40954
UniProt ID
P47989
EC Number
EC 1.17.3.2
Sequence
MTADKLVFFVNGRKVVEKNADPETTLLAYLRRKLGLSGTKLGCGEGGCGACTVMLSKYDR
LQNKIVHFSANACLAPICSLHHVAVTTVEGIGSTKTRLHPVQERIAKSHGSQCGFCTPGI
VMSMYTLLRNQPEPTMEEIENAFQGNLCRCTGYRPILQGFRTFARDGGCCGGDGNNPNCC
MNQKKDHSVSLSPSLFKPEEFTPLDPTQEPIFPPELLRLKDTPRKQLRFEGERVTWIQAS
TLKELLDLKAQHPDAKLVVGNTEIGIEMKFKNMLFPMIVCPAWIPELNSVEHGPDGISFG
AACPLSIVEKTLVDAVAKLPAQKTEVFRGVLEQLRWFAGKQVKSVASVGGNIITASPISD
LNPVFMASGAKLTLVSRGTRRTVQMDHTFFPGYRKTLLSPEEILLSIEIPYSREGEYFSA
FKQASRREDDIAKVTSGMRVLFKPGTTEVQELALCYGGMANRTISALKTTQRQLSKLWKE
ELLQDVCAGLAEELHLPPDAPGGMVDFRCTLTLSFFFKFYLTVLQKLGQENLEDKCGKLD
PTFASATLLFQKDPPADVQLFQEVPKGQSEEDMVGRPLPHLAADMQASGEAVYCDDIPRY
ENELSLRLVTSTRAHAKIKSIDTSEAKKVPGFVCFISADDVPGSNITGICNDETVFAKDK
VTCVGHIIGAVVADTPEHTQRAAQGVKITYEELPAIITIEDAIKNNSFYGPELKIEKGDL
KKGFSEADNVVSGEIYIGGQEHFYLETHCTIAVPKGEAGEMELFVSTQNTMKTQSFVAKM
LGVPANRIVVRVKRMGGGFGGKETRSTVVSTAVALAAYKTGRPVRCMLDRDEDMLITGGR
HPFLARYKVGFMKTGTVVALEVDHFSNVGNTQDLSQSIMERALFHMDNCYKIPNIRGTGR
LCKTNLPSNTAFRGFGGPQGMLIAECWMSEVAVTCGMPAEEVRRKNLYKEGDLTHFNQKL
EGFTLPRCWEECLASSQYHARKSEVDKFNKENCWKKRGLCIIPTKFGISFTVPFLNQAGA
LLHVYTDGSVLLTHGGTEMGQGLHTKMVQVASRALKIPTSKIYISETSTNTVPNTSPTAA
SVSADLNGQAVYAACQTILKRLEPYKKKNPSGSWEDWVTAAYMDTVSLSATGFYRTPNLG
YSFETNSGNPFHYFSYGVACSEVEIDCLTGDHKNLRTDIVMDVGSSLNPAIDIGQVEGAF
VQGLGLFTLEELHYSPEGSLHTRGPSTYKIPAFGSIPIEFRVSLLRDCPNKKAIYASKAV
GEPPLFLAASIFFAIKDAIRAARAQHTGNNVKELFRLDSPATPEKIRNACVDKFTTLCVT
GVPENCKPWSVRV
Drugs and Mode of Action
Drug(s) Allopurinol Drug Info Approved Hyperuricemia [1], [2]
Febuxostat Drug Info Approved Hyperuricaemia in gout [3], [4]
Curcumin Drug Info Phase 3 Cancer [5], [6]
Oxypurinol Drug Info Phase 2/3 Heart failure [7]
Cyclic pyranopterin monophosphate Drug Info Phase 2 Encephalopathy [8]
Topiroxostat Drug Info Phase 2 Gout [9]
LC-350189 Drug Info Phase 1 Gout [10]
BOF-4272 Drug Info Discontinued in Phase 2 Gout [11]
Y-700 Drug Info Discontinued in Phase 2 Gout [12]
Inhibitor 1,2,3,4,6-penta-O-galloyl-beta-D-glucose Drug Info [13]
1-(3-Cyano-phenyl)-1H-pyrazole-4-carboxylic acid Drug Info [14]
2-chloro-6(methylamino)purine Drug Info [15]
3,4'-(1H-1,2,4-triazole-3,5-diyl)dipyridine Drug Info [16]
3,5-bis(2-methylpyridin-4-yl)-1H-1,2,4-triazole Drug Info [16]
3,5-di(pyridin-4-yl)-1H-1,2,4-triazole Drug Info [16]
3-O-METHYLQUERCETIN Drug Info [17]
ACACETIN Drug Info [17]
Allopurinol Drug Info [18], [19], [20]
AMENTOFLAVONE Drug Info [17]
Aom-0763 Drug Info [21]
BAICALEIN Drug Info [17]
BOF-4272 Drug Info [22], [23]
CHRYSOERIOL Drug Info [17]
Curcumin Drug Info [24]
DIHYDROKAEMPFEROL Drug Info [17]
Dioxothiomolybdenum(VI) ion Drug Info [25]
Febuxostat Drug Info [3], [26]
Flavin-Adenine Dinucleotide Drug Info [27]
FUKUGETIN Drug Info [17]
LC-350189 Drug Info [28]
LIQUIRTIGENIN Drug Info [17]
NC-2500 Drug Info [21]
Oxypurinol Drug Info [29]
PERSICARIN Drug Info [17]
ROBINETIN Drug Info [17]
SCUTELLAREIN Drug Info [17]
Topiroxostat Drug Info [30]
WOGONIN Drug Info [17]
Y-700 Drug Info [31]
Cofactor Cyclic pyranopterin monophosphate Drug Info [32]
Pathways
BioCyc Pathway Purine nucleotides degradation
Urate biosynthesis/inosine 5&#039
-phosphate degradation
Guanosine nucleotides degradation
Adenosine nucleotides degradation
Retinoate biosynthesis II
KEGG Pathway Purine metabolism
Caffeine metabolism
Drug metabolism - other enzymes
Metabolic pathways
Peroxisome
PANTHER Pathway Adenine and hypoxanthine salvage pathway
Purine metabolism
PathWhiz Pathway Caffeine Metabolism
Purine Metabolism
Reactome Purine catabolism
WikiPathways Oxidative Stress
Effects of Nitric Oxide
Metabolism of nucleotides
Selenium Micronutrient Network
References
REF 1FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 018659.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6795).
REF 3Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.
REF 4(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6817).
REF 5Nanocurcumin: a promising therapeutic advancement over native curcumin. Crit Rev Ther Drug Carrier Syst. 2013;30(4):331-68.
REF 6(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7000).
REF 7ClinicalTrials.gov (NCT00063687) Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure. U.S. National Institutes of Health.
REF 8ClinicalTrials.gov (NCT02047461) Safety & Efficacy Study of ALXN1101 in Pediatric Patients With MoCD Type A Currently Treated With rcPMP. U.S. National Institutes of Health.
REF 9ClinicalTrials.gov (NCT02327754) Effect of Topiroxostat on Urinary Albumin Excretion Early Stage Diabetic Nephropathy and Hyperuricemia With or Without Gout. U.S. National Institutes of Health.
REF 10ClinicalTrials.gov (NCT01361646) Safety, Tolerability and Pharmacokinetic/Pharmacodynamic Characteristics of LC350189. U.S. National Institutes of Health.
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002649)
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010582)
REF 13Pentagalloylglucose, a xanthine oxidase inhibitor from a Paraguayan crude drug, "Molle-i" (Schinus terebinthifolius). J Nat Prod. 1989 Jan-Feb;52(1):210-1.
REF 14Bioorg Med Chem Lett. 2001 Apr 9;11(7):879-82.Synthesis and structure-activity relationships of 1-phenylpyrazoles as xanthine oxidase inhibitors.
REF 15Bioorg Med Chem. 2007 May 15;15(10):3450-6. Epub 2007 Mar 12.The screening and characterization of 6-aminopurine-based xanthine oxidase inhibitors.
REF 16Bioorg Med Chem Lett. 2009 Nov 1;19(21):6225-9. Epub 2009 Sep 2.Discovery of 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051 - a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia [corrected].
REF 17Inhibition of cow's milk xanthine oxidase by flavonoids. J Nat Prod. 1988 Mar-Apr;51(2):345-8.
REF 18Purification, crystallization and preliminary X-ray diffraction studies of xanthine dehydrogenase and xanthine oxidase isolated from bovine milk. Acta Crystallogr D Biol Crystallogr. 2000 Dec;56(Pt 12):1656-8.
REF 19Allopurinol: xanthine oxidase inhibitor. Tex Med. 1966 Jan;62(1):100-1.
REF 20Influence of postischemic administration of oxyradical antagonists on ischemic injury to rabbit skeletal muscle. Microsurgery. 1996;17(9):517-23.
REF 21(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2646).
REF 22Enantioselective uptake of BOF-4272, a xanthine oxidase inhibitor with a chiral sulfoxide, by isolated rat hepatocytes. Yakugaku Zasshi. 2001 Dec;121(12):989-94.
REF 23Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 24J Nat Prod. 2009 Apr;72(4):725-31.Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin, and curcumin.
REF 25DrugBank 3.0: a comprehensive resource for 'omics' research on drugs. Nucleic Acids Res. 2011 Jan;39(Database issue):D1035-4. Nucleic Acids Res. 2011 January
REF 26Clinical pipeline report, company report or official report of Takeda (2009).
REF 27How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 28Pharmacokinetics, pharmacodynamics, and tolerability of LC350189, a novel xanthine oxidase inhibitor, in healthy subjects. Drug Des Devel Ther. 2015 Aug 31;9:5033-49.
REF 29Oxypurinol as an inhibitor of xanthine oxidase-catalyzed production of superoxide radical. Biochem Pharmacol. 1988 Jan 15;37(2):349-52.
REF 30QT/QTc study conducted in Japanese adult healthy subjects: a novel xanthine oxidase inhibitor topiroxostat was not associated with QT prolongation. J Clin Pharmacol. 2014 Apr;54(4):446-52.
REF 31The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 32Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics. 2010 May;125(5):e1249-54.

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