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XDH  -  xanthine dehydrogenase

Bos taurus

 
 
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Disease relevance of XDH

  • Rhodobacter capsulatus xanthine dehydrogenase (XDH) forms an (alphabeta)2 heterotetramer and is highly homologous to homodimeric eukaryotic XDHs [1].
  • We have developed an efficient system for the recombinant expression of R. capsulatus XDH in Escherichia coli [1].
  • The conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO) and the reaction of XO-derived partially reduced oxygen species (PROS) have been suggested to be important in diverse mechanisms of tissue pathophysiology, including oxygen toxicity [2].
  • Thus the increased XDH/XO activity observed in response to hypoxia in the present study was due to posttranslational modulation of the enzyme [3].
 

High impact information on XDH

  • In mammals, xanthine oxidoreductase is synthesized as a dehydrogenase (XDH) but can be readily converted to its oxidase form (XO) either by proteolysis or modification of cysteine residues [4].
  • Here we identify a unique cluster of amino acids that plays a dual role by forming the core of a relay system for the XDH/XO transition and by gating a solvent channel leading toward the FAD ring [4].
  • The crystal structures of bovine milk XDH and XO demonstrated that atoms in the highly charged active-site loop (Gln-423-Lys-433) around the FAD cofactor underwent large dislocations during the conversion, blocking the approach of the NAD+ substrate to FAD in the XO form as well as changing the electrostatic environment around FAD [4].
  • Cleavage of surface-exposed loops of XDH causes major structural rearrangement of another loop close to the flavin ring (Gln 423Lys 433) [5].
  • Mammalian xanthine oxidoreductases, which catalyze the last two steps in the formation of urate, are synthesized as the dehydrogenase form xanthine dehydrogenase (XDH) but can be readily converted to the oxidase form xanthine oxidase (XO) by oxidation of sulfhydryl residues or by proteolysis [5].
 

Chemical compound and disease context of XDH

 

Biological context of XDH

  • This increase was not detectable in the presence of actinomycin D but was further induced in the presence of cycloheximide, consistent with the major site of XDH/XO up-regulation occurring at the transcriptional level [7].
  • Steady-state kinetics of xanthine/oxygen and NADH/oxygen turnover of XDH were determined to have kcat values of 2.1 +/- 0.1 and 2.5 +/- 0.9 s-1, respectively, at 25 degrees C, pH 7 [8].
  • Studies have been made on the possible involvement of malondialdehyde (MDA) and (E)-4-hydroxynon-2-enal (HNE), two terminal compounds of lipid peroxidation, in modifying xanthine oxidoreductase activity through interaction with the oxidase (XO) and/or dehydrogenase (XDH) forms [9].
 

Anatomical context of XDH

  • METHODS AND RESULTS: H2O2 (100 micromol/L) decreased bovine aortic endothelial cell (BAEC) XDH protein expression, and metabolic labeling studies indicated that H2O2 stimulated conversion of XDH to XO [10].
  • In addition, XDH-to-XO conversion was blocked by 2-APB and NO donors and induced by thapsigargin and M-3M3FBS, implicating phospholipase C and endoplasmic reticulum calcium stores in this process [10].
  • The results indicate that TNF, IFN-gamma, IL-6, IL-1, and dexamethasone induce XDH/XO activity in bovine renal epithelial cells (MDBK) [7].
 

Associations of XDH with chemical compounds

  • BAPTA-AM prevented the decline in XDH by H2O2, indicating that it was calcium-dependent [10].
  • In keeping with calcium acting downstream of H2O2, the calcium ionophore A23187 (1 micromol/L) caused XDH-to-XO conversion, and this was not prevented by the antioxidants [10].
  • The decline in XDH was mimicked by the reactive oxygen species (ROS) generating compounds SIN-1 and Menadione, as well as by stimulating BAECs with angiotensin II (200 nmol/L) [10].
  • It is concluded that nitric oxide reacts with an essential sulfur of the reduced molybdenum center of XO and XDH to produce desulfo-type inactive enzymes [11].
  • By Northern analysis, all cytokines and dexamethasone increased the level of the 5-kb XDH/XO mRNA [7].
 

Analytical, diagnostic and therapeutic context of XDH

  • The Kd for the binding of NAD to XDH was determined to be 280 +/- 145 microM by ultrafiltration and 160 +/- 40 microM by isothermal titration calorimetry [12].
  • The binding of NAD to oxidized XO and XDH was investigated by ultrafiltration and isothermal titration calorimetry [12].
  • Metabolic labeling and immunoprecipitation revealed the increase in XDH/XO activity requires new protein synthesis [7].
  • Similarly, no difference was noted in XDH/XO protein expression after hypoxic exposure, as determined by Western blot analysis [3].

References

  1. Recombinant Rhodobacter capsulatus xanthine dehydrogenase, a useful model system for the characterization of protein variants leading to xanthinuria I in humans. Leimkuhler, S., Hodson, R., George, G.N., Rajagopalan, K.V. J. Biol. Chem. (2003) [Pubmed]
  2. The contribution of vascular endothelial xanthine dehydrogenase/oxidase to oxygen-mediated cell injury. Panus, P.C., Wright, S.A., Chumley, P.H., Radi, R., Freeman, B.A. Arch. Biochem. Biophys. (1992) [Pubmed]
  3. Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia. Poss, W.B., Huecksteadt, T.P., Panus, P.C., Freeman, B.A., Hoidal, J.R. Am. J. Physiol. (1996) [Pubmed]
  4. Unique amino acids cluster for switching from the dehydrogenase to oxidase form of xanthine oxidoreductase. Kuwabara, Y., Nishino, T., Okamoto, K., Matsumura, T., Eger, B.T., Pai, E.F., Nishino, T. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  5. Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion. Enroth, C., Eger, B.T., Okamoto, K., Nishino, T., Nishino, T., Pai, E.F. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Protein film voltammetry of Rhodobacter capsulatus xanthine dehydrogenase. Aguey-Zinsou, K.F., Bernhardt, P.V., Leimkühler, S. J. Am. Chem. Soc. (2003) [Pubmed]
  7. Xanthine dehydrogenase and xanthine oxidase activity and gene expression in renal epithelial cells. Cytokine and steroid regulation. Pfeffer, K.D., Huecksteadt, T.P., Hoidal, J.R. J. Immunol. (1994) [Pubmed]
  8. The reaction of reduced xanthine dehydrogenase with molecular oxygen. Reaction kinetics and measurement of superoxide radical. Harris, C.M., Massey, V. J. Biol. Chem. (1997) [Pubmed]
  9. Mechanisms of action of malondialdehyde and 4-hydroxynonenal on xanthine oxidoreductase. Cighetti, G., Bortone, L., Sala, S., Allevi, P. Arch. Biochem. Biophys. (2001) [Pubmed]
  10. Regulation of xanthine oxidoreductase protein expression by hydrogen peroxide and calcium. McNally, J.S., Saxena, A., Cai, H., Dikalov, S., Harrison, D.G. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  11. Inhibition of xanthine oxidase and xanthine dehydrogenase by nitric oxide. Nitric oxide converts reduced xanthine-oxidizing enzymes into the desulfo-type inactive form. Ichimori, K., Fukahori, M., Nakazawa, H., Okamoto, K., Nishino, T. J. Biol. Chem. (1999) [Pubmed]
  12. Role of the flavin midpoint potential and NAD binding in determining NAD versus oxygen reactivity of xanthine oxidoreductase. Harris, C.M., Sanders, S.A., Massey, V. J. Biol. Chem. (1999) [Pubmed]
 
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