|
|
| Line 3: |
Line 3: |
| | <StructureSection load='7m32' size='340' side='right'caption='[[7m32]], [[Resolution|resolution]] 1.82Å' scene=''> | | <StructureSection load='7m32' size='340' side='right'caption='[[7m32]], [[Resolution|resolution]] 1.82Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7m32]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Pig Pig]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7M32 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M32 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7m32]] 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=7M32 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7M32 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALA:ALANINE'>ALA</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FNR:1-DEOXY-1-(7,8-DIMETHYL-2,4-DIOXO-3,4-DIHYDRO-2H-BENZO[G]PTERIDIN-1-ID-10(5H)-YL)-5-O-PHOSPHONATO-D-RIBITOL'>FNR</scene>, <scene name='pdbligand=LEU:LEUCINE'>LEU</scene>, <scene name='pdbligand=PRO:PROLINE'>PRO</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene>, <scene name='pdbligand=URA:URACIL'>URA</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]] 1.82Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">DPYD ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9823 PIG])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ALA:ALANINE'>ALA</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=FNR:1-DEOXY-1-(7,8-DIMETHYL-2,4-DIOXO-3,4-DIHYDRO-2H-BENZO[G]PTERIDIN-1-ID-10(5H)-YL)-5-O-PHOSPHONATO-D-RIBITOL'>FNR</scene>, <scene name='pdbligand=LEU:LEUCINE'>LEU</scene>, <scene name='pdbligand=PRO:PROLINE'>PRO</scene>, <scene name='pdbligand=SF4:IRON/SULFUR+CLUSTER'>SF4</scene>, <scene name='pdbligand=URA:URACIL'>URA</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Dihydropyrimidine_dehydrogenase_(NADP(+)) Dihydropyrimidine dehydrogenase (NADP(+))], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.2 1.3.1.2] </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=7m32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m32 OCA], [https://pdbe.org/7m32 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m32 RCSB], [https://www.ebi.ac.uk/pdbsum/7m32 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m32 ProSAT]</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=7m32 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7m32 OCA], [https://pdbe.org/7m32 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7m32 RCSB], [https://www.ebi.ac.uk/pdbsum/7m32 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7m32 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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>
| + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 25: |
Line 24: |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Pig]] | + | [[Category: Sus scrofa]] |
| - | [[Category: Beaupre, B]] | + | [[Category: Beaupre B]] |
| - | [[Category: Butrin, A]] | + | [[Category: Butrin A]] |
| - | [[Category: Forouzesh, D]] | + | [[Category: Forouzesh D]] |
| - | [[Category: Liu, D]] | + | [[Category: Liu D]] |
| - | [[Category: Moran, G]] | + | [[Category: Moran G]] |
| - | [[Category: Dihydropyrimidine dehydrogenase]]
| + | |
| - | [[Category: Dpd]]
| + | |
| - | [[Category: Fad]]
| + | |
| - | [[Category: Flavin]]
| + | |
| - | [[Category: Flavoprotein]]
| + | |
| - | [[Category: Fmn]]
| + | |
| - | [[Category: Ligand]]
| + | |
| - | [[Category: Mutant]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Soaking]]
| + | |
| - | [[Category: Uracil]]
| + | |
| Structural highlights
7m32 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 1.82Å |
| 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]
Publication Abstract from PubMed
The native function of dihydropyrimidine dehydrogenase (DPD) is to reduce the 5,6-vinylic bond of pyrimidines uracil and thymine with electrons obtained from NADPH. NADPH and pyrimidines bind at separate active sites separated by approximately 60 A that are bridged by four Fe4S4 centers. We have shown that DPD undergoes reductive activation, taking up two electrons from NADPH [Beaupre, B. A., et al. (2020) Biochemistry 59, 2419-2431]. pH studies indicate that the rate of turnover is not controlled by the protonation state of the general acid, cysteine 671. The activation of the C671 variants is delineated into two phases particularly at low pH values. Spectral deconvolution of the delineated reductive activation reaction reveals that the initial phase results in the accumulation of charge transfer absorption added to the binding difference spectrum for NADPH. The second phase results in reduction of one of the two flavins. X-ray crystal structure analysis of the C671S variant soaked with NADPH and the slow substrate, thymine, in a low-oxygen atmosphere resolved the presumed activated form of the enzyme that has the FMN cofactor reduced. These data reveal that charge transfer arises from the proximity of the NADPH and FAD bases and that the ensuing flavin is a result of rapid transfer of electrons to the FMN without accumulation of reduced forms of the FAD or Fe4S4 centers. These data suggest that the slow rate of turnover of DPD is governed by the movement of a mobile structural feature that carries the C671 residue.
Perturbing the Movement of Hydrogens to Delineate and Assign Events in the Reductive Activation and Turnover of Porcine Dihydropyrimidine Dehydrogenase.,Beaupre BA, Forouzesh DC, Butrin A, Liu D, Moran GR Biochemistry. 2021 Jun 8;60(22):1764-1775. doi: 10.1021/acs.biochem.1c00243. Epub, 2021 May 25. PMID:34032117[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Beaupre BA, Forouzesh DC, Butrin A, Liu D, Moran GR. Perturbing the Movement of Hydrogens to Delineate and Assign Events in the Reductive Activation and Turnover of Porcine Dihydropyrimidine Dehydrogenase. Biochemistry. 2021 Jun 8;60(22):1764-1775. doi: 10.1021/acs.biochem.1c00243. Epub, 2021 May 25. PMID:34032117 doi:http://dx.doi.org/10.1021/acs.biochem.1c00243
|
