4uhx: Difference between revisions

Latest revision as of 10:29, 10 January 2024

Human aldehyde oxidase in complex with phthalazine and thioridazine

Structural highlights

4uhx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:	4FT, FAD, FES, LZU, MLI, MOS, MTE, RTZ
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

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^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zientek M, Jiang Y, Youdim K, Obach RS. In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos. 2010 Aug;38(8):1322-7. doi: 10.1124/dmd.110.033555. Epub 2010 , May 5. PMID:20444863 doi:https://dx.doi.org/10.1124/dmd.110.033555
↑ Hutzler JM, Yang YS, Albaugh D, Fullenwider CL, Schmenk J, Fisher MB. Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes. Drug Metab Dispos. 2012 Feb;40(2):267-75. doi: 10.1124/dmd.111.042861. Epub 2011 , Oct 26. PMID:22031625 doi:https://dx.doi.org/10.1124/dmd.111.042861
↑ Hartmann T, Terao M, Garattini E, Teutloff C, Alfaro JF, Jones JP, Leimkuhler S. The impact of single nucleotide polymorphisms on human aldehyde oxidase. Drug Metab Dispos. 2012 May;40(5):856-64. doi: 10.1124/dmd.111.043828. Epub 2012 , Jan 25. PMID:22279051 doi:https://dx.doi.org/10.1124/dmd.111.043828
↑ Strelevitz TJ, Orozco CC, Obach RS. Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance. Drug Metab Dispos. 2012 Jul;40(7):1441-8. doi: 10.1124/dmd.112.045195. Epub 2012 , Apr 20. PMID:22522748 doi:https://dx.doi.org/10.1124/dmd.112.045195
↑ Barr JT, Jones JP. Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase. Drug Metab Dispos. 2013 Jan;41(1):24-9. doi: 10.1124/dmd.112.048546. Epub 2012, Sep 20. PMID:22996261 doi:https://dx.doi.org/10.1124/dmd.112.048546
↑ Fu C, Di L, Han X, Soderstrom C, Snyder M, Troutman MD, Obach RS, Zhang H. Aldehyde oxidase 1 (AOX1) in human liver cytosols: quantitative characterization of AOX1 expression level and activity relationship. Drug Metab Dispos. 2013 Oct;41(10):1797-804. doi: 10.1124/dmd.113.053082. Epub, 2013 Jul 15. PMID:23857892 doi:https://dx.doi.org/10.1124/dmd.113.053082
↑ Beedham C, Critchley DJ, Rance DJ. Substrate specificity of human liver aldehyde oxidase toward substituted quinazolines and phthalazines: a comparison with hepatic enzyme from guinea pig, rabbit, and baboon. Arch Biochem Biophys. 1995 Jun 1;319(2):481-90. PMID:7786031 doi:https://dx.doi.org/10.1006/abbi.1995.1320
↑ Rashidi MR, Smith JA, Clarke SE, Beedham C. In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver. Drug Metab Dispos. 1997 Jul;25(7):805-13. PMID:9224775
↑ Coelho C, Foti A, Hartmann T, Santos-Silva T, Leimkuhler S, Romao MJ. Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase. Nat Chem Biol. 2015 Aug 31. doi: 10.1038/nchembio.1895. PMID:26322824 doi:https://dx.doi.org/10.1038/nchembio.1895

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OCA

[1] Zientek M, Jiang Y, Youdim K, Obach RS. In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase. Drug Metab Dispos. 2010 Aug;38(8):1322-7. doi: 10.1124/dmd.110.033555. Epub 2010 , May 5. PMID:20444863 doi:https://dx.doi.org/10.1124/dmd.110.033555

[2] Hutzler JM, Yang YS, Albaugh D, Fullenwider CL, Schmenk J, Fisher MB. Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes. Drug Metab Dispos. 2012 Feb;40(2):267-75. doi: 10.1124/dmd.111.042861. Epub 2011 , Oct 26. PMID:22031625 doi:https://dx.doi.org/10.1124/dmd.111.042861

[3] Hartmann T, Terao M, Garattini E, Teutloff C, Alfaro JF, Jones JP, Leimkuhler S. The impact of single nucleotide polymorphisms on human aldehyde oxidase. Drug Metab Dispos. 2012 May;40(5):856-64. doi: 10.1124/dmd.111.043828. Epub 2012 , Jan 25. PMID:22279051 doi:https://dx.doi.org/10.1124/dmd.111.043828

[4] Strelevitz TJ, Orozco CC, Obach RS. Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes: estimation of the contribution of aldehyde oxidase to metabolic clearance. Drug Metab Dispos. 2012 Jul;40(7):1441-8. doi: 10.1124/dmd.112.045195. Epub 2012 , Apr 20. PMID:22522748 doi:https://dx.doi.org/10.1124/dmd.112.045195

[5] Barr JT, Jones JP. Evidence for substrate-dependent inhibition profiles for human liver aldehyde oxidase. Drug Metab Dispos. 2013 Jan;41(1):24-9. doi: 10.1124/dmd.112.048546. Epub 2012, Sep 20. PMID:22996261 doi:https://dx.doi.org/10.1124/dmd.112.048546

[6] Fu C, Di L, Han X, Soderstrom C, Snyder M, Troutman MD, Obach RS, Zhang H. Aldehyde oxidase 1 (AOX1) in human liver cytosols: quantitative characterization of AOX1 expression level and activity relationship. Drug Metab Dispos. 2013 Oct;41(10):1797-804. doi: 10.1124/dmd.113.053082. Epub, 2013 Jul 15. PMID:23857892 doi:https://dx.doi.org/10.1124/dmd.113.053082

[7] Beedham C, Critchley DJ, Rance DJ. Substrate specificity of human liver aldehyde oxidase toward substituted quinazolines and phthalazines: a comparison with hepatic enzyme from guinea pig, rabbit, and baboon. Arch Biochem Biophys. 1995 Jun 1;319(2):481-90. PMID:7786031 doi:https://dx.doi.org/10.1006/abbi.1995.1320

[8] Rashidi MR, Smith JA, Clarke SE, Beedham C. In vitro oxidation of famciclovir and 6-deoxypenciclovir by aldehyde oxidase from human, guinea pig, rabbit, and rat liver. Drug Metab Dispos. 1997 Jul;25(7):805-13. PMID:9224775

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

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@@ Line 4: / Line 4: @@
 == 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='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>
+</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>

4uhx: Difference between revisions

Latest revision as of 10:29, 10 January 2024

Human aldehyde oxidase in complex with phthalazine and thioridazine

Structural highlights

Function

Publication Abstract from PubMed

References

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