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Information on EC 1.17.1.4 - xanthine dehydrogenase and Organism(s) Homo sapiens and UniProt Accession P47989
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1.17.1.4 xanthine dehydrogenaseIUBMB Comments
Acts on a variety of purines and aldehydes, including hypoxanthine. The mammalian enzyme can also convert all-trans retinol to all-trans-retinoate, while the substrate is bound to a retinoid-binding protein . The enzyme from eukaryotes contains [2Fe-2S], FAD and a molybdenum centre. The mammalian enzyme predominantly exists as the NAD-dependent dehydrogenase (EC 1.17.1.4). During purification the enzyme is largely converted to an O2-dependent form, xanthine oxidase (EC 1.17.3.2). The conversion can be triggered by several mechanisms, including the oxidation of cysteine thiols to form disulfide bonds [2,6,8,15] [which can be catalysed by EC 1.8.4.7, enzyme-thiol transhydrogenase (glutathione-disulfide) in the presence of glutathione disulfide] or limited proteolysis, which results in irreversible conversion. The conversion can also occur in vivo [2,7,15].
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Word Map
- 1.17.1.4
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uric
-
1.2.1.37
-
1.1.1.204
- allopurinol
- environmental protection
-
ureide
-
1.1.3.22
- medicine
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1.2.3.1
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xanthinuria
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oxypurines
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butyrophilins
- synthesis
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hypouricemic
- agriculture
- biotechnology
- analysis
- nutrition
- molecular biology
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
xdh/xo, xanthine dehydrogenase/oxidase, atxdh1, paoabc, xanthine:nad+ oxidoreductase, xanthine-nad oxidoreductase, xanthine/nad+ oxidoreductase, xanthine dehydrogenase-1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
NAD-xanthine dehydrogenase
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-
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Rosy locus protein
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-
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xanthine oxidoreductase
xanthine-NAD oxidoreductase
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-
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xanthine/NAD+ oxidoreductase
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-
-
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XDH/XO
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-
-
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XOR
xanthine oxidoreductase
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-
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XOR
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-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
xanthine + NAD+ + H2O = urate + NADH + H+
reaction mechanism with substrate all-trans-retinol, overview
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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-
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
BRENDA
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-, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
xanthine:NAD+ oxidoreductase
Acts on a variety of purines and aldehydes, including hypoxanthine. The mammalian enzyme can also convert all-trans retinol to all-trans-retinoate, while the substrate is bound to a retinoid-binding protein [14]. The enzyme from eukaryotes contains [2Fe-2S], FAD and a molybdenum centre. The mammalian enzyme predominantly exists as the NAD-dependent dehydrogenase (EC 1.17.1.4). During purification the enzyme is largely converted to an O2-dependent form, xanthine oxidase (EC 1.17.3.2). The conversion can be triggered by several mechanisms, including the oxidation of cysteine thiols to form disulfide bonds [2,6,8,15] [which can be catalysed by EC 1.8.4.7, enzyme-thiol transhydrogenase (glutathione-disulfide) in the presence of glutathione disulfide] or limited proteolysis, which results in irreversible conversion. The conversion can also occur in vivo [2,7,15].
CAS REGISTRY NUMBER
COMMENTARY
9054-84-6
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
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xanthine oxidoreductase plays a physiological role in milk equal in importance to its catalytic function as an enzyme
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-
?
additional information
?
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xanthine dehydrogenase is the native form of xanthine oxidase, EC 1.17.3.2, conversion causes a loss of the NAD+ binding activity and of the retinol oxidation activity, the conversion with conformational changes is reversible, except for alteration due to proteolytic cleavage
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-
?
additional information
?
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xanthine dehydrogenase, XDH, can be converted to xanthine oxidase, XO, by a highly sophisticated mechanism, overview. The transition seems to involve a thermodynamic equilibrium between XDH and XO, disulfide bond formation or proteolysis can then lock the enzyme in the XO form. XDH and XO forms are in a thermodynamic equilibrium with a relatively low energy barrier between the two forms
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?
additional information
?
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The enzyme catalyzes the oxidation of purines, pterin and aldehydes with NAD+ or NADP+ as electron acceptor, and in some species can be transformed to xanthine oxidase (EC 1.17.3.2, XOD) capable of utilizing oxygen as the electron acceptor
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
xanthine oxidoreductase plays a physiological role in milk equal in importance to its catalytic function as an enzyme
-
-
?
additional information
?
-
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xanthine dehydrogenase is the native form of xanthine oxidase, EC 1.17.3.2, conversion causes a loss of the NAD+ binding activity and of the retinol oxidation activity, the conversion with conformational changes is reversible, except for alteration due to proteolytic cleavage
-
-
?
additional information
?
-
-
xanthine dehydrogenase, XDH, can be converted to xanthine oxidase, XO, by a highly sophisticated mechanism, overview. The transition seems to involve a thermodynamic equilibrium between XDH and XO, disulfide bond formation or proteolysis can then lock the enzyme in the XO form. XDH and XO forms are in a thermodynamic equilibrium with a relatively low energy barrier between the two forms
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
[2Fe-2S]-center
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XDH consists of 3 redox center domains, one of which contains 2 distinct iron-sulfur clusters ([2Fe-2S])
additional information
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cofactor domain amino acid sequence comparisons, overview. XDH consists of 3 redox center domains, XDH consists of 3 redox center domains, one of which contains 2 distinct iron-sulfur clusters ([2Fe-2S]), another that includes a flavin adenine dinucleotide (FAD), and a third that incorporates a sulfurated molybdenum cofactor (Moco). The [2Fe-2S] domain is more conserved than the Moco domain, and the FAD domain is the least conserved one between different species
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Iron
enzyme is about 30% deficient in iron-sulfur centers on basis of UV/vis and CD spectra
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
17beta-estradiol
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inhibition of enzyme activity in malignant and non-malignant mammary epithelial cells
4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile
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i.e. FYX-051, inhibition of xanthine oxidoreductase. In vivo, the inhibitor is modified by N1- and N2-glucuronidation, mainly catalyzed by UDP-glucuronosyltransferase UGT1A9
allopurinol
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inhibition of xanthine oxidoreductase also suppresses high tidal volume mechanical ventilation-induced alveolar apoptosis
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
kinetics in presence and absence of cellular retinol binding proteins, apo-CRBP and apo-CRABP, overview
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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xanthine oxidoreductase is activated in a p38 MAP kinase-dependent manner following high tidal volume mechanical ventilation and is involved in resulting increased alveolar cell apoptosis
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constitutive expression and high activity of XDH in non-malignant cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
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XDHs are widely distributed in all eukarya, bacteria and archaea domains, phylogenetic analysis
malfunction
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the retinoic acid deficiency in breast tumour epithelial cells has been ascribed to an insufficient expression of either the enzyme(s) involved in its biosynthesis or the cellular retinol binding protein or both, overview
physiological function
physiological function
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xanthine oxidoreductase catalyzes the oxidation of hypoxanthine to xanthine or xanthine to uric acid in the metabolic pathway of purine degradation
physiological function
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XDHs play significant roles in various cellular processes, including purine catabolism and production of reactive oxygen species (ROS) and nitric oxide (NO) in both physiological and pathological contexts
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). XDH_HUMAN
1333
0
146424
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
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structural comparison of xanthine dehydrogenase and xanthine oxidase, EC 1.17.3.2, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
mutant E803V, decrease in activity towards purine substrates is not due to large conformational change in the mutant protein
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E803V
R881M
E803V
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almost complete loss of activity with hypoxanthine, weak activity with xanthine, significant aldehyde oxidase activity
E803V
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very low steady-state activity towards xanthine or hypoxanthine, loss of hydrogen bonding with one of these residues greatly influences the electron transfer process to the molybdenum center, changing the rate-limiting step in the reductive half-reaction
R881M
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almost complete loss of activity with xanthine, weak activity with hypoxanthine, significant aldehyde oxidase activity
R881M
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very low steady-state activity towards xanthine or hypoxanthine, loss of hydrogen bonding with one of these residues greatly influences the electron transfer process to the molybdenum center, changing the rate-limiting step in the reductive half-reaction
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4
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liver extract: conversion of dehydrogenase to oxidase activity, some loss of activity after 7 days, extract from cerebrellum and cerebral cortex: stable for 7 days
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
downregulation of enzyme expression in malignant and non-malignant mammary epithelial cells by 17beta-estradiol
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
environmental protection
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XDHs can find applications in environmental degradation of pollutants like aldehydes and industrial application in nucleoside drugs like ribavirin
medicine
medicine
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demonstration of a functional link between xanthine oxidoreductase expression and mammary epithelial cell migration, potential role in enzyme in suppressing breast cancer pathogenesis. Level of xanthine oxidoreductase is markedly reduced in highly invasive mammary tumor cells, and over-expression of enzyme cDNA in cell lines possessing weak expression and high migratory capacity inhibits their migration in vitro
medicine
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the enzyme inhibitor 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile, i.e. FYX-051, is modified in vivo by N1- and N2-glucuronidation, mainly catalyzed by UDP-glucuronosyltransferase UGT1A9
medicine
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xanthine oxidoreductase is activated in a p38 MAP kinase-dependent manner following high tidal volume mechanical ventilation and is involved in resulting increased alveolar cell apoptosis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wajner, M.; Harkness, R.A.
Distribution of xanthine dehydrogenase and oxidase activities in human and rabbit tissues
Biochem. Soc. Trans.
16
358-359
1988
Oryctolagus cuniculus, Homo sapiens
-
Wajner, M.; Harkness, R.A.
Distribution of xanthine dehydrogenase and oxidase activities in human and rabbit tissues
Biochim. Biophys. Acta
991
79-84
1989
Homo sapiens, Oryctolagus cuniculus
Wright, R.M.; Vaitaitis, G.M.; Wilson, C.M.; Repine, T.B.; Terada, L.S.; Repine, J.E.
cDNA cloning, characterization, and tissue-specific expression of human xanthine dehydrogenase/xanthine oxidase
Proc. Natl. Acad. Sci. USA
90
10690-10694
1993
Homo sapiens
Benboubetra, M.; Baghiani, A.; Atmani, D.; Harrison, R.
Physicochemical and kinetic properties of purified sheep's milk xanthine oxidoreductase
J. Dairy Sci.
87
1580-1584
2004
Bos taurus, Capra hircus, Homo sapiens, Ovis aries
Godber, B.L.; Schwarz, G.; Mendel, R.R.; Lowe, D.J.; Bray, R.C.; Eisenthal, R.; Harrison, R.
Molecular characterization of human xanthine oxidoreductase: the enzyme is grossly deficient in molybdenum and substantially deficient in iron-sulphur centres
Biochem. J.
388
501-508
2005
Bos taurus, Homo sapiens (P47989)
Yamaguchi, Y.; Matsumura, T.; Ichida, K.; Okamoto, K.; Nishino, T.
Human Xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: roles of active site residues in binding and activation of purine substrate
J. Biochem.
141
513-524
2007
Homo sapiens
Omura, K.; Nakazawa, T.; Sato, T.; Iwanaga, T.; Nagata, O.
Characterization of N-glucuronidation of 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl) pyridine-2-carbonitrile (FYX-051): a new xanthine oxidoreductase inhibitor
Drug Metab. Dispos.
35
2143-2148
2007
Homo sapiens
Le, A.; Damico, R.; Damarla, M.; Boueiz, A.; Pae, H.H.; Skirball, J.; Hasan, E.; Peng, X.; Chesley, A.; Crow, M.T.; Reddy, S.P.; Tuder, R.M.; Hassoun, P.M.
Alveolar cell apoptosis is dependent on p38-MAPK-mediated activation of xanthine oxidoreductase in ventilator-induced lung injury
J. Appl. Physiol.
105
1282-1290
2008
Homo sapiens
Fini, M.A.; Orchard-Webb, D.; Kosmider, B.; Amon, J.D.; Kelland, R.; Shibao, G.; Wright, R.M.
Migratory activity of human breast cancer cells is modulated by differential expression of xanthine oxidoreductase
J. Cell. Biochem.
1005
1008-1026
2008
Homo sapiens, Mus musculus
Nishino, T.; Okamoto, K.; Eger, B.T.; Pai, E.F.; Nishino, T.
Mammalian xanthine oxidoreductase - mechanism of transition from xanthine dehydrogenase to xanthine oxidase
FEBS J.
275
3278-3289
2008
Bos taurus, Gallus gallus, Homo sapiens, Rattus norvegicus, Rhodobacter capsulatus
Taibi, G.; Carruba, G.; Miceli, V.; Cocciadiferro, L.; Nicotra, C.M.
Estradiol decreases xanthine dehydrogenase enzyme activity and protein expression in non-tumorigenic and malignant human mammary epithelial cells
J. Cell. Biochem.
108
688-692
2009
Homo sapiens
Taibi, G.; Di Gaudio, F.; Nicotra, C.M.
Xanthine dehydrogenase processes retinol to retinoic acid in human mammary epithelial cells
J. Enzyme Inhib. Med. Chem.
23
317-327
2008
Homo sapiens
Wang, C.H.; Zhang, C.; Xing, X.H.
Xanthine dehydrogenase an old enzyme with new knowledge and prospects
Bioengineered
7
395-405
2016
Acinetobacter baumannii, Acinetobacter phage Ab105-3phi, Arabidopsis thaliana (Q8GUQ8), Arthrobacter luteolus, Bos taurus, Clostridium cylindrosporum, Drosophila melanogaster, Enterobacter cloacae, Escherichia coli (Q46799 AND Q46800), Gallus gallus, Homo sapiens, Micrococcus sp., Ovis aries, Pseudomonas putida, Rattus norvegicus, Rhodobacter capsulatus, Rhodobacter capsulatus B10XDHB, Streptomyces cyanogenus
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