5epg

From Proteopedia

(Difference between revisions)

Current revision

Human aldehyde oxidase SNP S1271L

Structural highlights

5epg 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 3.39Å
Ligands:	, , ,
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 (AOX1) is an enzyme with a broad substrate specificity, catalyzing the oxidation of a wide range of endogenous and exogenous aldehydes as well as N-heterocyclic aromatic compounds. In humans, the enzyme has been recognized with an emerging importance in phase I drug metabolism. However, the true physiological function of AOX1 in mammals is still unknown. Further, numerous single-nucleotide polymorphisms (SNPs) have been identified in human AOX1. SNPs are a major source of inter-individual variability in the human population and SNP-based amino acid exchanges in AOX1 were reported to modulate the catalytic function of the enzyme in either a positive or negative fashion. For the reliable analysis of the effect of amino acid exchanges in human proteins, the existence of reproducible expression systems for the production of active protein in ample amounts for kinetic, spectroscopic and crystallographic studies is required. In our study we report an optimized expression system for hAOX1 in Escherichia coli using a codon-optimized construct. The codon-optimization resulted in an up to 15-fold increase of protein production and a simplified purification procedure. Using the optimized expression system three SNPs were studied, resulting in amino acid changes C44W, G1269R and S1271L. In addition, the crystal structure of the S1271L SNP was solved. We demonstrate that the recombinant enzyme can be used for future studies to exploit the role of AOX in drug metabolism, and for the identification and synthesis of new drugs targeting AOX in combination with crystallographic and modeling studies.

Optimization of the expression of Human Aldehyde Oxidase for Investigations of Single Nucleotide Polymorphisms.,Foti A, Hartmann T, Coelho C, Santos-Silva T, Romao MJ, Leimkuhler S Drug Metab Dispos. 2016 Feb 3. pii: dmd.115.068395. PMID:26842593^[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
↑ Foti A, Hartmann T, Coelho C, Santos-Silva T, Romao MJ, Leimkuhler S. Optimization of the expression of Human Aldehyde Oxidase for Investigations of Single Nucleotide Polymorphisms. Drug Metab Dispos. 2016 Feb 3. pii: dmd.115.068395. PMID:26842593 doi:http://dx.doi.org/10.1124/dmd.115.068395

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/5epg"

Categories: Homo sapiens | Large Structures | Coelho C | Romao MJ | Santos-Silva T

@@ Line 1: / Line 1: @@
 ==Human aldehyde oxidase SNP S1271L==
-<StructureSection load='5epg' size='340' side='right' caption='[[5epg]], [[Resolution|resolution]] 3.39&Aring;' scene=''>
+<StructureSection load='5epg' size='340' side='right'caption='[[5epg]], [[Resolution|resolution]] 3.39&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5epg]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EPG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EPG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5epg]] 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=5EPG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EPG 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=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></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]] 3.39&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4uhw|4uhw]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</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></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=5epg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5epg OCA], [http://pdbe.org/5epg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5epg RCSB], [http://www.ebi.ac.uk/pdbsum/5epg PDBsum]</span></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=5epg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5epg OCA], [https://pdbe.org/5epg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5epg RCSB], [https://www.ebi.ac.uk/pdbsum/5epg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5epg ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://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>
+[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 ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Coelho, C]]
+[[Category: Homo sapiens]]
-[[Category: Romao, M J]]
+[[Category: Large Structures]]
-[[Category: Santos-Silva, T]]
+[[Category: Coelho C]]
-[[Category: Drug metabolism]]
+[[Category: Romao MJ]]
-[[Category: Oxidoreductase]]
+[[Category: Santos-Silva T]]
-[[Category: Snp]]

5epg

From Proteopedia

Current revision

Human aldehyde oxidase SNP S1271L

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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