Crystal structures of the active and alloxanthine-inhibited forms of xanthine dehydrogenase from Rhodobacter capsulatus.
Xanthine dehydrogenase (XDH), a complex molybdo/iron-sulfur/flavoprotein, catalyzes the oxidation of hypoxanthine to xanthine followed by oxidation of xanthine to uric acid with concomitant reduction of NAD+. The 2.7 A resolution structure of Rhodobacter capsulatus XDH reveals that the bacterial and bovine XDH have highly similar folds despite differences in subunit composition. The NAD+ binding pocket of the bacterial XDH resembles that of the dehydrogenase form of the bovine enzyme rather than that of the oxidase form, which reduces O(2) instead of NAD+. The drug allopurinol is used to treat XDH-catalyzed uric acid build-up occurring in gout or during cancer chemotherapy. As a hypoxanthine analog, it is oxidized to alloxanthine, which cannot be further oxidized but acts as a tight binding inhibitor of XDH. The 3.0 A resolution structure of the XDH-alloxanthine complex shows direct coordination of alloxanthine to the molybdenum via a nitrogen atom. These results provide a starting point for the rational design of new XDH inhibitors.
Truglio
James J
JJ
Department of Pharmacological Sciences, Center for Structural Biology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Theis
Karsten
K
Leimkühler
Silke
S
Rappa
Roberto
R
Rajagopalan
K V
KV
Kisker
Caroline
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010117:Oxypurinol / Q000378:metabolism; D020836:Protein Structure, Quaternary; D016354:Rhodobacter capsulatus / Q000201:enzymology*; D016415:Sequence Alignment; D014968:Xanthine Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
D004791:Enzyme Inhibitors; D014968:Xanthine Dehydrogenase; D010117:Oxypurinol