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[[Image:1h7x.gif|left|200px]]<br /><applet load="1h7x" size="350" color="white" frame="true" align="right" spinBox="true"
caption="1h7x, resolution 2.01&Aring;" />
'''DIHYDROPYRIMIDINE DEHYDROGENASE (DPD) FROM PIG, TERNARY COMPLEX OF A MUTANT ENZYME (C671A), NADPH AND 5-FLUOROURACIL'''<br />


==Overview==
==Dihydropyrimidine dehydrogenase (DPD) from pig, ternary complex of a mutant enzyme (C671A), NADPH and 5-fluorouracil==
Dihydropyrimidine dehydrogenase catalyzes the first step in pyrimidine, degradation: the NADPH-dependent reduction of uracil and thymine to the, corresponding 5,6-dihydropyrimidines. Its controlled inhibition has become, an adjunct target for cancer therapy, since the enzyme is also responsible, for the rapid breakdown of the chemotherapeutic drug 5-fluorouracil. The, crystal structure of the homodimeric pig liver enzyme (2x 111 kDa), determined at 1.9 A resolution reveals a highly modular subunit, organization, consisting of five domains with different folds., Dihydropyrimidine dehydrogenase contains two FAD, two FMN and eight, [4Fe-4S] clusters, arranged in two electron transfer chains that pass the, dimer interface twice. Two of the Fe-S clusters show a hitherto unobserved, coordination involving a glutamine residue. The ternary complex of an, inactive mutant of the enzyme with bound NADPH and 5-fluorouracil reveals, the architecture of the substrate-binding sites and residues responsible, for recognition and binding of the drug.
<StructureSection load='1h7x' size='340' side='right'caption='[[1h7x]], [[Resolution|resolution]] 2.01&Aring;' scene=''>
 
== Structural highlights ==
==About this Structure==
<table><tr><td colspan='2'>[[1h7x]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H7X FirstGlance]. <br>
1H7X is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa] with <scene name='pdbligand=SF4:'>SF4</scene>, <scene name='pdbligand=FMN:'>FMN</scene>, <scene name='pdbligand=FAD:'>FAD</scene>, <scene name='pdbligand=NDP:'>NDP</scene> and <scene name='pdbligand=URF:'>URF</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Dihydropyrimidine_dehydrogenase_(NADP(+)) Dihydropyrimidine dehydrogenase (NADP(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.2 1.3.1.2] Known structural/functional Site: <scene name='pdbsite=AC5:Urf Binding Site For Chain D'>AC5</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H7X OCA].  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.01&#8491;</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=FMN:FLAVIN+MONONUCLEOTIDE'>FMN</scene>, <scene name='pdbligand=NDP:NADPH+DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NDP</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene>, <scene name='pdbligand=URF:5-FLUOROURACIL'>URF</scene></td></tr>
==Reference==
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1h7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h7x OCA], [https://pdbe.org/1h7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h7x RCSB], [https://www.ebi.ac.uk/pdbsum/1h7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h7x ProSAT]</span></td></tr>
Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil., Dobritzsch D, Schneider G, Schnackerz KD, Lindqvist Y, EMBO J. 2001 Feb 15;20(4):650-60. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11179210 11179210]
</table>
[[Category: Dihydropyrimidine dehydrogenase (NADP(+))]]
== Function ==
[[Category: Single protein]]
[https://www.uniprot.org/uniprot/DPYD_PIG DPYD_PIG] Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine.<ref>PMID:9860876</ref> <ref>PMID:20831907</ref> <ref>PMID:11179210</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/h7/1h7x_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=1h7x ConSurf].
<div style="clear:both"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Sus scrofa]]
[[Category: Sus scrofa]]
[[Category: Dobritzsch, D.]]
[[Category: Dobritzsch D]]
[[Category: Lindqvist, Y.]]
[[Category: Lindqvist Y]]
[[Category: Schnackerz, K.D.]]
[[Category: Schnackerz KD]]
[[Category: Schneider, G.]]
[[Category: Schneider G]]
[[Category: FAD]]
[[Category: FMN]]
[[Category: NDP]]
[[Category: SF4]]
[[Category: URF]]
[[Category: 5-fluorouracil degradation]]
[[Category: electron transfer]]
[[Category: flavin]]
[[Category: iron-sulfur clusters]]
[[Category: oxidoreductase]]
[[Category: pyrimidine catabolism]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:57:01 2008''

Latest revision as of 14:29, 27 March 2024

Dihydropyrimidine dehydrogenase (DPD) from pig, ternary complex of a mutant enzyme (C671A), NADPH and 5-fluorouracilDihydropyrimidine dehydrogenase (DPD) from pig, ternary complex of a mutant enzyme (C671A), NADPH and 5-fluorouracil

Structural highlights

1h7x is a 4 chain structure with sequence from Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.01Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DPYD_PIG Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine.[1] [2] [3]

Evolutionary Conservation

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

References

  1. ↑ Rosenbaum K, Jahnke K, Curti B, Hagen WR, Schnackerz KD, Vanoni MA. Porcine recombinant dihydropyrimidine dehydrogenase: comparison of the spectroscopic and catalytic properties of the wild-type and C671A mutant enzymes. Biochemistry. 1998 Dec 15;37(50):17598-609. PMID:9860876 doi:http://dx.doi.org/10.1021/bi9815997
  2. ↑ Lohkamp B, Voevodskaya N, Lindqvist Y, Dobritzsch D. Insights into the mechanism of dihydropyrimidine dehydrogenase from site-directed mutagenesis targeting the active site loop and redox cofactor coordination. Biochim Biophys Acta. 2010 Dec;1804(12):2198-206. doi:, 10.1016/j.bbapap.2010.08.014. Epub 2010 Sep 8. PMID:20831907 doi:http://dx.doi.org/10.1016/j.bbapap.2010.08.014
  3. ↑ Dobritzsch D, Schneider G, Schnackerz KD, Lindqvist Y. Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil. EMBO J. 2001 Feb 15;20(4):650-60. PMID:11179210 doi:10.1093/emboj/20.4.650

1h7x, resolution 2.01Å

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