User:Adam Mirando/Sandbox 1: Difference between revisions

<scene name='User:Adam_Mirando/Sandbox_1/Fad_domain/4'>FAD</scene> coenzyme. In XDH the electrons are then passed preferentially from the reduced [http://en.wikipedia.org/wiki/FAD flavin] to a final [http://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide NAD⁺] acceptor, creating NADH <ref name="thermo" />. Apart from NADH, XDH may also use O₂ as a final electron acceptor. In contrast, conversion to the XO form precludes NAD⁺ from binding, permitting only the use of O₂. The reduction of O₂ produces substantial amounts of H₂O₂ and superoxide as byproducts <ref name="gluarg" /><ref name="conver">PMID:15878860</ref>.  The prodution of these oxidative species has been implicated in the innate immune response <ref>PMID:12967676</ref> and cardiovascular disease, such as [http://en.wikipedia.org/wiki/Atherosclerosis atherosclerosis] <ref>PMID:12958034</ref>, [http://en.wikipedia.org/wiki/Reperfusion_injury ischemia-reperfusion injury], and chronic heart failure <ref>PMID:14694147</ref> <ref>PMID:12105162</ref>.

Several mechanisms have been suggested for the oxidation of xanthine to urate by xanthine oxidoreductase. However, a substantial amount of data appears to favor a mechanism in which a deprotonated molybdenum hydroxyl attacks the C8 atom of xanthine. This mechanism begins with the extraction of a proton from the hydroxyl of the molybdenum center by Glu1261 <ref>PMID:15265866</ref>, an event computed to occur readily in the presence of the substrate <ref name="theoretical">PMID:17564439</ref>. The electrons from the deprotonated oxygen are then free to attack the electrophilic C8 atom of the bound <scene name='User:Adam_Mirando/Sandbox_1/Xanthine_in_active_site/1'>xanthine</scene>. The formation of glutamic acid stabilizes this structure through hydrogen bond interactions with the N1 atom <ref>PMID:15148401</ref>. Crystalographic data has also suggested possible stabilizing interactions between Arg880 of the active site and enolate tautomerization at C6 <ref name="SubOri">PMID:19109252</ref>. Bond formation between the substrate and the molybdenum center orients a Mo = S moiety equatorially to the substrate, positioning it favorably for a concomitant hydride transfer from xanthine N7 <ref name="gluarg">PMID:18513323</ref>. Extraction of this hydride produces Mo-SH and reduces the Mo center from Mo VI to Mo IV. This intermediate breaks down through electron transfer from the molybdenum center through the iron-sulfur clusters, known as Fe-S I and Fe-S II to the bound FAD, forming FADH₂. In this mechanism the Fe-S clusters function as electron sinks, maintaining an oxidized Mo-cofactor and a reduced FADH₂. The Mo atom serves as a transducer between the two electrons passed from the substrate to the single electron of system of the Fe-S clusters.  The transfer of electrons can be monitored through the formation of the paramagnetic transient Mo V <ref>PMID:15134930</ref>. Subsequent reduction of NAD⁺ to NADH in the case of xanthine dehydrogenases and O₂ to H₂O₂ regenerates the oxidized FAD. Other mechanisms involving protonated molybdenum hydroxyls have been proposed with similar calculated activation energies (40 kcal/mol). However, the products in these cases have been computationally determined to be less stable that the reactant complex <ref name="theoretical" />.