spacer
spacer

PDBsum entry 1v97

Go to PDB code: 
protein ligands metals Protein-protein interface(s) links
Oxidoreductase PDB id
1v97
Jmol
Contents
Protein chains
1298 a.a. *
Ligands
FES ×4
MTE-MOS ×2
FAD ×2
FYX ×2
ACY ×2
GOL ×8
Metals
_CA ×2
Waters ×2082
* Residue conservation analysis
PDB id:
1v97
Name: Oxidoreductase
Title: Crystal structure of bovine milk xanthine dehydrogenase fyx- form
Structure: Xanthine dehydrogenase. Chain: a, b. Synonym: xd. Ec: 1.1.1.204
Source: Bos taurus. Cattle. Organism_taxid: 9913
Biol. unit: Dimer (from PQS)
Resolution:
1.94Å     R-factor:   0.178     R-free:   0.208
Authors: K.Okamoto,K.Matsumoto,R.Hille,B.T.Eger,E.F.Pai,T.Nishino
Key ref:
K.Okamoto et al. (2004). The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition. Proc Natl Acad Sci U S A, 101, 7931-7936. PubMed id: 15148401 DOI: 10.1073/pnas.0400973101
Date:
21-Jan-04     Release date:   22-Jun-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P80457  (XDH_BOVIN) -  Xanthine dehydrogenase/oxidase
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1332 a.a.
1298 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 1: E.C.1.17.1.4  - Xanthine dehydrogenase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
Xanthine Dehydrogenase
      Reaction:
1. Xanthine + NAD+ + H2O = urate + NADH
2. Hypoxanthine + NAD+ + H2O = xanthine + NADH
Xanthine
Bound ligand (Het Group name = MTE)
matches with 45.83% similarity
+ NAD(+)
+ H(2)O
= urate
+ NADH
Hypoxanthine
+ NAD(+)
+ H(2)O
=
xanthine
Bound ligand (Het Group name = MTE)
matches with 45.83% similarity
+ NADH
      Cofactor: FAD; Iron-sulfur; Mo cation
FAD
Bound ligand (Het Group name = FAD) corresponds exactly
Iron-sulfur
Mo cation
   Enzyme class 2: E.C.1.17.3.2  - Xanthine oxidase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
      Reaction: Xanthine + H2O + O2 = urate + H2O2
Xanthine
+ H(2)O
+ O(2)
= urate
+ H(2)O(2)
      Cofactor: FAD; Iron-sulfur; Molybdopterin
FAD
Bound ligand (Het Group name = FAD) corresponds exactly
Iron-sulfur
Molybdopterin
Bound ligand (Het Group name = MTE) corresponds exactly
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   3 terms 
  Biological process     oxidation-reduction process   2 terms 
  Biochemical function     catalytic activity     13 terms  

 

 
    reference    
 
 
DOI no: 10.1073/pnas.0400973101 Proc Natl Acad Sci U S A 101:7931-7936 (2004)
PubMed id: 15148401  
 
 
The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition.
K.Okamoto, K.Matsumoto, R.Hille, B.T.Eger, E.F.Pai, T.Nishino.
 
  ABSTRACT  
 
Molybdenum is widely distributed in biology and is usually found as a mononuclear metal center in the active sites of many enzymes catalyzing oxygen atom transfer. The molybdenum hydroxylases are distinct from other biological systems catalyzing hydroxylation reactions in that the oxygen atom incorporated into the product is derived from water rather than molecular oxygen. Here, we present the crystal structure of the key intermediate in the hydroxylation reaction of xanthine oxidoreductase with a slow substrate, in which the carbon-oxygen bond of the product is formed, yet the product remains complexed to the molybdenum. This intermediate displays a stable broad charge-transfer band at approximately 640 nm. The crystal structure of the complex indicates that the catalytically labile Mo-OH oxygen has formed a bond with a carbon atom of the substrate. In addition, the MoS group of the oxidized enzyme has become protonated to afford Mo-SH on reduction of the molybdenum center. In contrast to previous assignments, we find this last ligand at an equatorial position in the square-pyramidal metal coordination sphere, not the apical position. A water molecule usually seen in the active site of the enzyme is absent in the present structure, which probably accounts for the stability of this intermediate toward ligand displacement by hydroxide.
 
  Selected figure(s)  
 
Figure 4.
Fig. 4. Stereo representation of the structure in the active site of XDH with bound FYX-051. FYX-051 (magenta), molybdopterin (cyan), and catalytically important amino acid residues (CPK-atom colored) are illustrated as stick models on a ribbon model background.
Figure 7.
Fig. 7. Proposed mechanism initiated by base-assisted nucleophilic attack of Mo--OH on heterocycles, with subsequent hydride transfer to produce the reaction intermediate (c) whose structure has been analyzed in this report. The subsequent oxidation occurs via d or/and e with varying ratio depending on the substrate used.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21120472 J.Jin, A.J.Straathof, M.W.Pinkse, and U.Hanefeld (2011).
Purification, characterization, and cloning of a bifunctional molybdoenzyme with hydratase and alcohol dehydrogenase activity.
  Appl Microbiol Biotechnol, 89, 1831-1840.  
21170563 L.B.Maia, and J.J.Moura (2011).
Nitrite reduction by xanthine oxidase family enzymes: a new class of nitrite reductases.
  J Biol Inorg Chem, 16, 443-460.  
21442756 M.Leigh, C.E.Castillo, D.J.Raines, and A.K.Duhme-Klair (2011).
Synthesis, activity testing and molybdenum(VI) complexation of Schiff bases derived from 2,4,6-trihydroxybenzaldehyde investigated as xanthine oxidase inhibitors.
  ChemMedChem, 6, 612-616.  
21105859 N.Ashizawa, T.Shimo, K.Matsumoto, T.Taniguchi, M.Moto, and O.Nagata (2011).
Establishment of simultaneous treatment model with citrate for preventing nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor, in rats.
  Drug Chem Toxicol, 34, 151-161.  
20936465 T.Shimo, N.Ashizawa, M.Moto, T.Iwanaga, and O.Nagata (2011).
Study on species differences in nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor.
  Arch Toxicol, 85, 505-512.  
20059399 L.M.Blank, B.E.Ebert, K.Buehler, and B.Bühler (2010).
Redox biocatalysis and metabolism: molecular mechanisms and metabolic network analysis.
  Antioxid Redox Signal, 13, 349-394.  
19741035 J.F.Alfaro, C.A.Joswig-Jones, W.Ouyang, J.Nichols, G.J.Crouch, and J.P.Jones (2009).
Purification and mechanism of human aldehyde oxidase expressed in Escherichia coli.
  Drug Metab Dispos, 37, 2393-2398.  
19452052 M.J.Romão (2009).
Molybdenum and tungsten enzymes: a crystallographic and mechanistic overview.
  Dalton Trans, (), 4053-4068.  
19109249 U.Dietzel, J.Kuper, J.A.Doebbler, A.Schulte, J.J.Truglio, S.Leimkühler, and C.Kisker (2009).
Mechanism of Substrate and Inhibitor Binding of Rhodobacter capsulatus Xanthine Dehydrogenase.
  J Biol Chem, 284, 8768-8776.
PDB codes: 2w3r 2w3s 2w54 2w55
18998731 J.F.Alfaro, and J.P.Jones (2008).
Studies on the mechanism of aldehyde oxidase and xanthine oxidase.
  J Org Chem, 73, 9469-9472.  
18360072 K.Okamoto, and T.Nishino (2008).
Crystal structures of mammalian xanthine oxidoreductase bound with various inhibitors: allopurinol, febuxostat, and FYX-051.
  J Nippon Med Sch, 75, 2-3.  
18036331 M.Li, T.A.Müller, B.A.Fraser, and R.P.Hausinger (2008).
Characterization of active site variants of xanthine hydroxylase from Aspergillus nidulans.
  Arch Biochem Biophys, 470, 44-53.  
18328078 Q.Gao, and J.S.Thorson (2008).
The biosynthetic genes encoding for the production of the dynemicin enediyne core in Micromonospora chersina ATCC53710.
  FEMS Microbiol Lett, 282, 105-114.  
18354776 S.Chaves, M.Gil, S.Canário, R.Jelic, M.J.Romão, J.Trincão, E.Herdtweck, J.Sousa, C.Diniz, P.Fresco, and M.A.Santos (2008).
Biologically relevant O,S-donor compounds. Synthesis, molybdenum complexation and xanthine oxidase inhibition.
  Dalton Trans, (), 1773-1782.  
18513323 T.Nishino, K.Okamoto, B.T.Eger, E.F.Pai, and T.Nishino (2008).
Mammalian xanthine oxidoreductase - mechanism of transition from xanthine dehydrogenase to xanthine oxidase.
  FEBS J, 275, 3278-3289.  
17139522 A.Thapper, D.R.Boer, C.D.Brondino, J.J.Moura, and M.J.Romão (2007).
Correlating EPR and X-ray structural analysis of arsenite-inhibited forms of aldehyde oxidoreductase.
  J Biol Inorg Chem, 12, 353-366.
PDB code: 3l4p
17429948 G.M.Montero-Morán, M.Li, E.Rendòn-Huerta, F.Jourdan, D.J.Lowe, A.W.Stumpff-Kane, M.Feig, C.Scazzocchio, and R.P.Hausinger (2007).
Purification and characterization of the FeII- and alpha-ketoglutarate-dependent xanthine hydroxylase from Aspergillus nidulans.
  Biochemistry, 46, 5293-5304.  
17511860 S.Kalra, G.Jena, K.Tikoo, and A.K.Mukhopadhyay (2007).
Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol.
  BMC Biochem, 8, 8.  
17964425 Y.C.Chang, F.W.Lee, C.S.Chen, S.T.Huang, S.H.Tsai, S.H.Huang, and C.M.Lin (2007).
Structure-activity relationship of C6-C3 phenylpropanoids on xanthine oxidase-inhibiting and free radical-scavenging activities.
  Free Radic Biol Med, 43, 1541-1551.  
16480912 C.D.Brondino, M.J.Romão, I.Moura, and J.J.Moura (2006).
Molybdenum and tungsten enzymes: the xanthine oxidase family.
  Curr Opin Chem Biol, 10, 109-114.  
16669776 G.Schwarz, and R.R.Mendel (2006).
Molybdenum cofactor biosynthesis and molybdenum enzymes.
  Annu Rev Plant Biol, 57, 623-647.  
16487068 H.Tamta, S.Kalra, and A.K.Mukhopadhyay (2006).
Biochemical characterization of some pyrazolopyrimidine-based inhibitors of xanthine oxidase.
  Biochemistry (Mosc), 71, S49-S54.  
17084874 N.Ashizawa, T.Shimo, K.Matsumoto, K.Oba, T.Nakazawa, and O.Nagata (2006).
Strain differences in the responsiveness between Sprague-Dawley and Fischer rats to nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor.
  Toxicol Appl Pharmacol, 217, 260-265.  
16507884 P.Pacher, A.Nivorozhkin, and C.Szabó (2006).
Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol.
  Pharmacol Rev, 58, 87.  
15948966 A.Cultrone, C.Scazzocchio, M.Rochet, G.Montero-Morán, C.Drevet, and R.Fernández-Martín (2005).
Convergent evolution of hydroxylation mechanisms in the fungal kingdom: molybdenum cofactor-independent hydroxylation of xanthine via alpha-ketoglutarate-dependent dioxygenases.
  Mol Microbiol, 57, 276-290.  
  16508115 D.R.Boer, A.Müller, S.Fetzner, D.J.Lowe, and M.J.Romão (2005).
On the purification and preliminary crystallographic analysis of isoquinoline 1-oxidoreductase from Brevundimonas diminuta 7.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 137-140.  
16206825 H.Tamta, R.Thilagavathi, A.K.Chakraborti, and A.K.Mukhopadhyay (2005).
6-(N-benzoylamino)purine as a novel and potent inhibitor of xanthine oxidase: inhibition mechanism and molecular modeling studies.
  J Enzyme Inhib Med Chem, 20, 317-324.  
16091936 M.Resch, H.Dobbek, and O.Meyer (2005).
Structural and functional reconstruction in situ of the [CuSMoO2] active site of carbon monoxide dehydrogenase from the carbon monoxide oxidizing eubacterium Oligotropha carboxidovorans.
  J Biol Inorg Chem, 10, 518-528.
PDB code: 1zxi
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.