Structural and conformational analysis of the oxidase to dehydrogenase conversion of xanthine oxidoreductase.

The Journal of Biological Chemistry
James L McManaman, David L Bain

Abstract

Xanthine oxidoreductase (XOR) is a 300-kDa homodimer that can exist as an NAD+-dependent dehydrogenase (XD) or as an O2-dependent oxidase (XO) depending on the oxidation state of its cysteine thiols. Both XD and XO undergo limited cleavage by chymotrypsin and trypsin. Trypsin selectively cleaved both enzyme forms at Lys184, while chymotrypsin cleaved XD primarily at Met181 but cleaved XO at Met181 and at Phe560. Chymotrypsin, but not trypsin, cleavage also prevented the reductive conversion of XO to XD; thus the region surrounding Phe560 appears to be important in the interconversion of the two forms. Size exclusion chromatography showed that disulfide bond formation reduced the hydrodynamic volume of the enzyme, and two-dimensional gel electrophoresis of chymotrypsin-digested XO showed significant, disulfide bond-mediated, conformational heterogeneity in the N-terminal third of the enzyme but no evidence of disulfide bonds between the N-terminal and C-terminal regions or between XOR subunits. These results indicate that intrasubunit disulfide bond formation leads to a global conformational change in XOR that results in the exposure of the region surrounding Phe560. Conformational changes within this region in turn appear to pl...Continue Reading

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Citations

Sep 29, 2004·Histochemistry and Cell Biology·Leni Moldovan, Nicanor I Moldovan
Dec 1, 2006·Journal of Mammary Gland Biology and Neoplasia·James L McManamanEdwin C Thrower
Nov 14, 2007·Journal of Mammary Gland Biology and Neoplasia·James L McManamanHorst Robenek
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