View source for 4uhx


==Human aldehyde oxidase in complex with phthalazine and thioridazine==
<StructureSection load='4uhx' size='340' side='right'caption='[[4uhx]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4uhx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UHX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UHX FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4FT:PHTHALAZINE'>4FT</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=LZU:10-{2-[(2S)-1-METHYLPIPERIDIN-2-YL]ETHYL}-2-(METHYLSULFANYL)-10H-PHENOTHIAZINE'>LZU</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=MOS:DIOXOTHIOMOLYBDENUM(VI)+ION'>MOS</scene>, <scene name='pdbligand=MTE:PHOSPHONIC+ACIDMONO-(2-AMINO-5,6-DIMERCAPTO-4-OXO-3,7,8A,9,10,10A-HEXAHYDRO-4H-8-OXA-1,3,9,10-TETRAAZA-ANTHRACEN-7-YLMETHYL)ESTER'>MTE</scene>, <scene name='pdbligand=RTZ:10-{2-[(2R)-1-METHYLPIPERIDIN-2-YL]ETHYL}-2-(METHYLSULFANYL)-10H-PHENOTHIAZINE'>RTZ</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4uhx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uhx OCA], [https://pdbe.org/4uhx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uhx RCSB], [https://www.ebi.ac.uk/pdbsum/4uhx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uhx ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AOXA_HUMAN AOXA_HUMAN] Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and N-methylphthalazinium, as well as aldehydes, such as benzaldehyde, retinal, pyridoxal, and vanillin. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Participates in the bioactivation of prodrugs such as famciclovir, catalyzing the oxidation step from 6-deoxypenciclovir to penciclovir, which is a potent antiviral agent. Is probably involved in the regulation of reactive oxygen species homeostasis. May be a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. Also may catalyze nitric oxide (NO) production via the reduction of nitrite to NO with NADH or aldehyde as electron donor. May play a role in adipogenesis.<ref>PMID:20444863</ref> <ref>PMID:22031625</ref> <ref>PMID:22279051</ref> <ref>PMID:22522748</ref> <ref>PMID:22996261</ref> <ref>PMID:23857892</ref> <ref>PMID:7786031</ref> <ref>PMID:9224775</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aldehyde oxidase (AOX) is a xanthine oxidase (XO)-related enzyme with emerging importance due to its role in the metabolism of drugs and xenobiotics. We report the first crystal structures of human AOX1, substrate free (2.6-A resolution) and in complex with the substrate phthalazine and the inhibitor thioridazine (2.7-A resolution). Analysis of the protein active site combined with steady-state kinetic studies highlight the unique features, including binding and substrate orientation at the active site, that characterize human AOX1 as an important drug-metabolizing enzyme. Structural analysis of the complex with the noncompetitive inhibitor thioridazine revealed a new, unexpected and fully occupied inhibitor-binding site that is structurally conserved among mammalian AOXs and XO. The new structural insights into the catalytic and inhibition mechanisms of human AOX that we now report will be of great value for the rational analysis of clinical drug interactions involving inhibition of AOX1 and for the prediction and design of AOX-stable putative drugs.

Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase.,Coelho C, Foti A, Hartmann T, Santos-Silva T, Leimkuhler S, Romao MJ Nat Chem Biol. 2015 Aug 31. doi: 10.1038/nchembio.1895. PMID:26322824<ref>PMID:26322824</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4uhx" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Coelho C]]
[[Category: Romao MJ]]
[[Category: Santos-Silva T]]