6q6q

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Revision as of 13:44, 10 May 2019

Human aldehyde oxidase SNP G1269R

Structural highlights

6q6q is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4uhx, 4uhw, 5epg
Gene:	AOX1, AO (HUMAN)
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

Human aldehyde oxidase (hAOX1) is a molybdenum enzyme with high toxicological importance, but its physiological role is still unknown. hAOX1 metabolizes different classes of xenobiotics and is one of the main drug-metabolizing enzymes in the liver, along with cytochrome P450. hAOX1 oxidizes and inactivates a large number of drug molecules and has been responsible for the failure of several phase I clinical trials. The interindividual variability of drug-metabolizing enzymes caused by single nucleotide polymorphisms (SNPs) is highly relevant in pharmaceutical treatments. In this study, we present the crystal structure of the inactive variant G1269R, revealing the first structure of a molybdenum cofactor (Moco)-free form of hAOX1. These data allowed to model, for the first time, the flexible Gate 1 that controls access to the active site. Furthermore, we inspected the thermostability of wild-type hAOX1 and hAOX1 with various SNPs (L438V, R1231H, G1269R or S1271L) by CD spectroscopy and ThermoFAD, revealing that amino acid exchanges close to the Moco site can impact protein stability up to 10 degrees C. These results correlated with biochemical and structural data and enhance our understanding of hAOX1 and the effect of SNPs in the gene encoding this enzyme in the human population. ENZYMES: Aldehyde oxidase (EC1.2.3.1); xanthine dehydrogenase (EC1.17.1.4); xanthine oxidase (EC1.1.3.2). DATABASES: Structural data are available in the Protein Data Bank under the accession number 6Q6Q.

Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms.,Mota C, Esmaeeli M, Coelho C, Santos-Silva T, Wolff M, Foti A, Leimkuhler S, Romao MJ FEBS Open Bio. 2019 May;9(5):925-934. doi: 10.1002/2211-5463.12617. Epub 2019 Apr, 15. PMID:30985987^[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:http://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:http://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:http://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:http://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:http://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:http://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:http://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
↑ Mota C, Esmaeeli M, Coelho C, Santos-Silva T, Wolff M, Foti A, Leimkuhler S, Romao MJ. Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms. FEBS Open Bio. 2019 May;9(5):925-934. doi: 10.1002/2211-5463.12617. Epub 2019 Apr, 15. PMID:30985987 doi:http://dx.doi.org/10.1002/2211-5463.12617

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6q6q"

@@ Line 3: / Line 3: @@
 <StructureSection load='6q6q' size='340' side='right'caption='[[6q6q]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6q6q]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q6Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q6Q FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6q6q]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q6Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6Q6Q FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4uhx|4uhx]], [[4uhw|4uhw]], [[5epg|5epg]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AOX1, AO ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6q6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q6q OCA], [http://pdbe.org/6q6q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q6q RCSB], [http://www.ebi.ac.uk/pdbsum/6q6q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q6q ProSAT]</span></td></tr>
 </table>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Large Structures]]
 [[Category: Coelho, C]]

6q6q

From Proteopedia

Revision as of 13:44, 10 May 2019

Human aldehyde oxidase SNP G1269R

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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