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[[Image:2e1q.jpg|left|200px]]<br /><applet load="2e1q" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2e1q, resolution 2.6&Aring;" />
'''Crystal Structure of Human Xanthine Oxidoreductase mutant, Glu803Val'''<br />


==Overview==
==Crystal Structure of Human Xanthine Oxidoreductase mutant, Glu803Val==
<StructureSection load='2e1q' size='340' side='right'caption='[[2e1q]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2e1q]] is a 4 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=2E1Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2E1Q 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]] 2.6&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FES:FE2/S2+(INORGANIC)+CLUSTER'>FES</scene>, <scene name='pdbligand=MOM:HYDROXY(DIOXO)MOLYBDENUM'>MOM</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=SAL:2-HYDROXYBENZOIC+ACID'>SAL</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=2e1q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2e1q OCA], [https://pdbe.org/2e1q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2e1q RCSB], [https://www.ebi.ac.uk/pdbsum/2e1q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2e1q ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/XDH_HUMAN XDH_HUMAN] Defects in XDH are the cause of xanthinuria type 1 (XU1) [MIM:[https://omim.org/entry/278300 278300]. Xanthinuria is characterized by excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. XU1 is due to isolated xanthine dehydrogenase. XU1 patients can metabolize allopurinol.<ref>PMID:9153281</ref> <ref>PMID:10844591</ref> <ref>PMID:11379872</ref> <ref>PMID:14551354</ref>
== Function ==
[https://www.uniprot.org/uniprot/XDH_HUMAN XDH_HUMAN] Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro).<ref>PMID:17301077</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/e1/2e1q_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2e1q ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Xanthine oxidase (oxidoreductase; XOR) and aldehyde oxidase (AO) are similar in protein structure and prosthetic group composition, but differ in substrate preference. Here we show that mutation of two amino acid residues in the active site of human XOR for purine substrates results in conversion of the substrate preference to AO type. Human XOR and its Glu803-to-valine (E803V) and Arg881-to-methionine (R881M) mutants were expressed in an Escherichia coli system. The E803V mutation almost completely abrogated the activity towards hypoxanthine as a substrate, but very weak activity towards xanthine remained. On the other hand, the R881M mutant lacked activity towards xanthine, but retained slight activity towards hypoxanthine. Both mutants, however, exhibited significant aldehyde oxidase activity. The crystal structure of E803V mutant of human XOR was determined at 2.6 A resolution. The overall molybdopterin domain structure of this mutant closely resembles that of bovine milk XOR; amino acid residues in the active centre pocket are situated at very similar positions and in similar orientations, except that Glu803 was replaced by valine, indicating that the decrease in activity towards purine substrate is not due to large conformational change in the mutant enzyme. Unlike wild-type XOR, the mutants were not subject to time-dependent inhibition by allopurinol.
Xanthine oxidase (oxidoreductase; XOR) and aldehyde oxidase (AO) are similar in protein structure and prosthetic group composition, but differ in substrate preference. Here we show that mutation of two amino acid residues in the active site of human XOR for purine substrates results in conversion of the substrate preference to AO type. Human XOR and its Glu803-to-valine (E803V) and Arg881-to-methionine (R881M) mutants were expressed in an Escherichia coli system. The E803V mutation almost completely abrogated the activity towards hypoxanthine as a substrate, but very weak activity towards xanthine remained. On the other hand, the R881M mutant lacked activity towards xanthine, but retained slight activity towards hypoxanthine. Both mutants, however, exhibited significant aldehyde oxidase activity. The crystal structure of E803V mutant of human XOR was determined at 2.6 A resolution. The overall molybdopterin domain structure of this mutant closely resembles that of bovine milk XOR; amino acid residues in the active centre pocket are situated at very similar positions and in similar orientations, except that Glu803 was replaced by valine, indicating that the decrease in activity towards purine substrate is not due to large conformational change in the mutant enzyme. Unlike wild-type XOR, the mutants were not subject to time-dependent inhibition by allopurinol.


==Disease==
Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: roles of active site residues in binding and activation of purine substrate.,Yamaguchi Y, Matsumura T, Ichida K, Okamoto K, Nishino T J Biochem. 2007 Apr;141(4):513-24. Epub 2007 Feb 14. PMID:17301077<ref>PMID:17301077</ref>
Known diseases associated with this structure: Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606350 606350]], Coenzyme Q10 deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606350 606350]]


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
2E1Q is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=BCT:'>BCT</scene>, <scene name='pdbligand=CA:'>CA</scene>, <scene name='pdbligand=FES:'>FES</scene>, <scene name='pdbligand=FAD:'>FAD</scene>, <scene name='pdbligand=MTE:'>MTE</scene>, <scene name='pdbligand=MOM:'>MOM</scene> and <scene name='pdbligand=SAL:'>SAL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2E1Q OCA].
</div>
 
<div class="pdbe-citations 2e1q" style="background-color:#fffaf0;"></div>
==Reference==
== References ==
Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: roles of active site residues in binding and activation of purine substrate., Yamaguchi Y, Matsumura T, Ichida K, Okamoto K, Nishino T, J Biochem. 2007 Apr;141(4):513-24. Epub 2007 Feb 14. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17301077 17301077]
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Ichida, K.]]
[[Category: Ichida K]]
[[Category: Matsumura, T.]]
[[Category: Matsumura T]]
[[Category: Nishino, T.]]
[[Category: Nishino T]]
[[Category: Okamoto, K.]]
[[Category: Okamoto K]]
[[Category: Yamaguchi, Y.]]
[[Category: Yamaguchi Y]]
[[Category: BCT]]
[[Category: CA]]
[[Category: FAD]]
[[Category: FES]]
[[Category: MOM]]
[[Category: MTE]]
[[Category: SAL]]
[[Category: 2fe-2s]]
[[Category: fad]]
[[Category: molybdenum cofactor]]
[[Category: oxidoreductase]]
[[Category: xanthine oxidase]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:04:54 2008''

Latest revision as of 11:33, 25 October 2023

Crystal Structure of Human Xanthine Oxidoreductase mutant, Glu803ValCrystal Structure of Human Xanthine Oxidoreductase mutant, Glu803Val

Structural highlights

2e1q is a 4 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 2.6Å
Ligands:, , , , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

XDH_HUMAN Defects in XDH are the cause of xanthinuria type 1 (XU1) [MIM:278300. Xanthinuria is characterized by excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. XU1 is due to isolated xanthine dehydrogenase. XU1 patients can metabolize allopurinol.[1] [2] [3] [4]

Function

XDH_HUMAN Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro).[5]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Xanthine oxidase (oxidoreductase; XOR) and aldehyde oxidase (AO) are similar in protein structure and prosthetic group composition, but differ in substrate preference. Here we show that mutation of two amino acid residues in the active site of human XOR for purine substrates results in conversion of the substrate preference to AO type. Human XOR and its Glu803-to-valine (E803V) and Arg881-to-methionine (R881M) mutants were expressed in an Escherichia coli system. The E803V mutation almost completely abrogated the activity towards hypoxanthine as a substrate, but very weak activity towards xanthine remained. On the other hand, the R881M mutant lacked activity towards xanthine, but retained slight activity towards hypoxanthine. Both mutants, however, exhibited significant aldehyde oxidase activity. The crystal structure of E803V mutant of human XOR was determined at 2.6 A resolution. The overall molybdopterin domain structure of this mutant closely resembles that of bovine milk XOR; amino acid residues in the active centre pocket are situated at very similar positions and in similar orientations, except that Glu803 was replaced by valine, indicating that the decrease in activity towards purine substrate is not due to large conformational change in the mutant enzyme. Unlike wild-type XOR, the mutants were not subject to time-dependent inhibition by allopurinol.

Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: roles of active site residues in binding and activation of purine substrate.,Yamaguchi Y, Matsumura T, Ichida K, Okamoto K, Nishino T J Biochem. 2007 Apr;141(4):513-24. Epub 2007 Feb 14. PMID:17301077[6]

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

References

  1. ↑ Ichida K, Amaya Y, Kamatani N, Nishino T, Hosoya T, Sakai O. Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J Clin Invest. 1997 May 15;99(10):2391-7. PMID:9153281 doi:10.1172/JCI119421
  2. ↑ Levartovsky D, Lagziel A, Sperling O, Liberman U, Yaron M, Hosoya T, Ichida K, Peretz H. XDH gene mutation is the underlying cause of classical xanthinuria: a second report. Kidney Int. 2000 Jun;57(6):2215-20. PMID:10844591 doi:10.1046/j.1523-1755.2000.00082.x
  3. ↑ Sakamoto N, Yamamoto T, Moriwaki Y, Teranishi T, Toyoda M, Onishi Y, Kuroda S, Sakaguchi K, Fujisawa T, Maeda M, Hada T. Identification of a new point mutation in the human xanthine dehydrogenase gene responsible for a case of classical type I xanthinuria. Hum Genet. 2001 Apr;108(4):279-83. PMID:11379872
  4. ↑ Gok F, Ichida K, Topaloglu R. Mutational analysis of the xanthine dehydrogenase gene in a Turkish family with autosomal recessive classical xanthinuria. Nephrol Dial Transplant. 2003 Nov;18(11):2278-83. PMID:14551354
  5. ↑ Yamaguchi Y, Matsumura T, Ichida K, Okamoto K, Nishino T. Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: roles of active site residues in binding and activation of purine substrate. J Biochem. 2007 Apr;141(4):513-24. Epub 2007 Feb 14. PMID:17301077 doi:10.1093/jb/mvm053
  6. ↑ Yamaguchi Y, Matsumura T, Ichida K, Okamoto K, Nishino T. Human xanthine oxidase changes its substrate specificity to aldehyde oxidase type upon mutation of amino acid residues in the active site: roles of active site residues in binding and activation of purine substrate. J Biochem. 2007 Apr;141(4):513-24. Epub 2007 Feb 14. PMID:17301077 doi:10.1093/jb/mvm053

2e1q, resolution 2.60Å

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