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Xanthine oxidase is one of the most useful molybdenum containing enzymes, which catalyzes a wide range of purine derivative heterocyclic substrates. In order for the interaction between the reactants to take place, the substrates are expected to enter the binding pocket and attain a proper orientation with the help of binding pocket amino acid residues. In addition to the binding pocket amino acids, there are several factors that affect the progression of substrates. Therefore, the study is mainly focused to identify the factors affecting the binding stage of catalysis. The activity of xanthine oxidase family enzymes greatly depends on the proper orientation of the substrates and their interaction sites. Therefore, the rate of formation of substrate- enzyme complex is proposed to be affected by the proper orientation and the interaction site of the substrate. Moreover, the keto and enol forms of substrates as well as the existence of the substituent groups affect the reactivity of xanthine oxidase. Thus, the rate of the reaction is proposed to be affected by these factors. The variable activities of the substrates towards xanthine oxidase enzyme are largely due to the factors that affect the reductive half-reaction such as proper orientation of substrates, binding sites, activation of the active site, toutomeric nature of substrates and the inductive and steric effects. This work is used to provide valuable information that may have a mechanistic importance in establishing the substrate preferences of bmXOR to RcXDH and AOR type of enzymes in order to relate electronic structure contributions to enzymatic catalysis.
Voityuk AA, Albert K, Roman JM, Huber R, Rosch N. Substrate oxidation in the active site of xanthine oxidase and related enzymes. A model density functional study. Inorg. Chem. 1997;37:176-180.
Bayse AC. Density-functional theory models of xanthine oxidoreductase activity: Comparison of substrate tautomerization and protonation. J. Chem. Soc. 2009;29: 2306-2314.
Pauff JM, Cao H, Hille R. substrate orientation and catalysis at the molybdenum site in xanthine oxidase. J. Biol. Chem. 2009;284:8760–8767.
Garattini E, Menedel R, Romao MJ, Wright R, Terao M. Mammalian molybdo–flavoenzymes, an expanding family of proteins: Structure, genetics, regulation, function and pathophysiology. Biochem. J. 2003;372:15-32.
Hernandez B, Luque JF, Orozco M. Tautomerism of xanthine oxidase substrates hypoxanthine and allopurinol. J. Org. Chem. 1996;61:5964-5971.
Greenlee L, Handle P. Xanthine oxidase: Influence of pH on substrate specificity. J. Biol. Chem. 1964;239:1090-1095.
Amano T, Ochi N, Sato H, Sakaki S. Oxidation reaction by xanthine oxidase. theoretical study of reaction mechanism. J. Am. Chem. Soc. 2007;129:8131-8138.
Zhang HX, Wu D. A theoretical study on the mechanism of the reductive half-reaction of xanthine oxidase. Inorg. Chem. 2005;44:1466-1471.
Bayse AC. Theoretical characterization of the “Very Rapid” Mo (V) species generated in the oxidation of xanthine oxidase. Inorg. Chem. 2005;45:2199-2202.
Enroth C, Eger TB, Okamoto K, Nishino T, Nishino T, Emil F, Pai EF. Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: Structure-based mechanism of conversion. J. Biol. Chem. 2000;97:10723-10728.
Yamaguchi Y, Matsumura T, Ichida K, Okamoto K, Takeshi 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. Biol. Chem. 2007;141:513–524.
Martz E. Protein explorer: Easy yet powerful macromolecular visualization, Trends in Biochem. Sci. 2002;27:107-109.
Pauff JM, Cao H, Hille R. Substrate orientation and catalytic specificity in the action of xanthine oxidase: The sequential hydroxylation of hypoxanthine to uric acid. J. Biol. Chem. 2010;284:8760-8767.
Pauff JM, Zhang J, Bell CE, Hille R. Substrate orientation in xanthine oxidase. J. Biol. Chem. 2008;283:4818–4824.
Pauff JM, Hemann CF, Hemann NJ, Leimkuhler S, Hille R. The role of argenine 310 in catalysis and substrate specificity in xanthine dehydrogenase from Rhodobacter capsulatus. J. Biol. Chem. 2007;282:12785–12790.
Romao MJ. Molybdenum and tungsten enzymes: A crystallographic and mechanistic Overview. J. Royal. Soc. 2009;17:4053-4068.
Hille R. Structure and function of xanthine oxidoreductase. Eur. J. Inorg. Chem. 2006;36:1913-1926.
Dinesh S, Shikha GW, Bhavana GW, Nidi S, Dileep S. Biological activities of purine analoges. Rev. J. Pharm. and Sci. Innov. 2012;1(2):29-34.
Pauff JM, Cao H, Hille R. Substrate orientation and the origin catalytic power in xanthine oxidoreductase. In. J. Chem. 2010;50:355-362.
Hille R, Nishino T. Xanthine oxidase and xanthine dehydrogenase. J. Bio Chem. 1995;9:995-1003.
Voityuk AA, Albert K, Stlmeier SK, Nasluzov VA, Neyman KM, Hof P, Huber R, Romao JM, Rosch N. Prediction of alternative structures of the molybdenum site in the xanthine oxidase-related aldehyde oxido reductase. J. Am. Chem. Soc. 1997;119:3159-3160.
Leimkuhler S, Stockert AL, Igarashi K, Nishino T, Hille R. The role of active site glutamate residues in catalysis of rhodobacter capsulatus xanthine dehydrogenase. J. Biol. Chem. 2004;279: 40437-40444.
Matsumoto K, Okamoto K, Hille R, Eger BT, Pai EF, Nishino T. The crystal structure of XOR during catalysis: Implications for reaction mechanism and enzyme inhibition. Proc. Nat. Acad. Sci. 2004;101:7931-7936.
Pauff JM, Zhang J, Bell CE, Hille R. Substrate orientation in xanthine oxidase crystal structure with HMP. J. Biol. Chem. 2007;6:1-16.
Becke ADJ. Density functional thermo chemistry 3: The role of exact exchange. J. Chem. Phys. 1993;98:5648-5652.
Lee C, Yang W, Parr RG. Development of the Colle-Salvetti conelation energy formula into a functional of the electron density. J. Phys. Rev. 1988;37:785-789.