5h4j: Difference between revisions
New page: '''Unreleased structure''' The entry 5h4j is ON HOLD Authors: Chong, K.T., Miyahara, S., Miyakoshi, H., Fukuoka, M. Description: Crystal structure of Human dUTPase in complex with N-[(... |
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==Crystal structure of Human dUTPase in complex with N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide== | |||
<StructureSection load='5h4j' size='340' side='right'caption='[[5h4j]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5h4j]] 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=5H4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5H4J 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]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=FKM:N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide'>FKM</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=5h4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5h4j OCA], [https://pdbe.org/5h4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5h4j RCSB], [https://www.ebi.ac.uk/pdbsum/5h4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5h4j ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/DUT_HUMAN DUT_HUMAN] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.<ref>PMID:8805593</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity. In addition, TAS-114 had moderate and reversible inhibitory activity on dihydropyrimidine dehydrogenase (DPD), a catabolizing enzyme of 5-FU. Thus, TAS-114 increased the bioavailability of 5-FU when coadministered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. Enhancement of antitumor efficacy caused by the addition of TAS-114 was retained in the presence of a potent DPD inhibitor containing oral fluoropyrimidine (S-1), indicating that dUTPase inhibition plays a major role in enhancing the antitumor efficacy of fluoropyrimidine-based therapy. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment. Mol Cancer Ther; 17(8); 1683-93. (c)2018 AACR. | |||
TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy.,Yano W, Yokogawa T, Wakasa T, Yamamura K, Fujioka A, Yoshisue K, Matsushima E, Miyahara S, Miyakoshi H, Taguchi J, Chong KT, Takao Y, Fukuoka M, Matsuo K Mol Cancer Ther. 2018 Aug;17(8):1683-1693. doi: 10.1158/1535-7163.MCT-17-0911., Epub 2018 May 10. PMID:29748212<ref>PMID:29748212</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5h4j" style="background-color:#fffaf0;"></div> | ||
[[Category: Fukuoka | |||
[[Category: Miyahara | ==See Also== | ||
[[Category: | *[[DUTPase 3D structures|DUTPase 3D structures]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chong KT]] | |||
[[Category: Fukuoka M]] | |||
[[Category: Miyahara S]] | |||
[[Category: Miyakoshi H]] | |||
Latest revision as of 10:23, 9 August 2023
Crystal structure of Human dUTPase in complex with N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamideCrystal structure of Human dUTPase in complex with N-[(1R)-1-[3-(Cyclopentyloxy)-phenyl]-ethyl]-3-[(3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl)methoxy]-1-propanesulfonamide
Structural highlights
FunctionDUT_HUMAN This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.[1] Publication Abstract from PubMed5-Fluorouracil (5-FU) is an antimetabolite and exerts antitumor activity via intracellularly and physiologically complicated metabolic pathways. In this study, we designed a novel small molecule inhibitor, TAS-114, which targets the intercellular metabolism of 5-FU to enhance antitumor activity and modulates catabolic pathway to improve the systemic availability of 5-FU. TAS-114 strongly and competitively inhibited deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), a gatekeeper protein preventing aberrant base incorporation into DNA, and enhanced the cytotoxicity of fluoropyrimidines in cancer cells; however, it had little intrinsic activity. In addition, TAS-114 had moderate and reversible inhibitory activity on dihydropyrimidine dehydrogenase (DPD), a catabolizing enzyme of 5-FU. Thus, TAS-114 increased the bioavailability of 5-FU when coadministered with capecitabine in mice, and it significantly improved the therapeutic efficacy of capecitabine by reducing the required dose of the prodrug by dual enzyme inhibition. Enhancement of antitumor efficacy caused by the addition of TAS-114 was retained in the presence of a potent DPD inhibitor containing oral fluoropyrimidine (S-1), indicating that dUTPase inhibition plays a major role in enhancing the antitumor efficacy of fluoropyrimidine-based therapy. In conclusion, TAS-114, a dual dUTPase/DPD inhibitor, demonstrated the potential to improve the therapeutic efficacy of fluoropyrimidine. Dual inhibition of dUTPase and DPD is a novel strategy for the advancement of oral fluoropyrimidine-based chemotherapy for cancer treatment. Mol Cancer Ther; 17(8); 1683-93. (c)2018 AACR. TAS-114, a First-in-Class Dual dUTPase/DPD Inhibitor, Demonstrates Potential to Improve Therapeutic Efficacy of Fluoropyrimidine-Based Chemotherapy.,Yano W, Yokogawa T, Wakasa T, Yamamura K, Fujioka A, Yoshisue K, Matsushima E, Miyahara S, Miyakoshi H, Taguchi J, Chong KT, Takao Y, Fukuoka M, Matsuo K Mol Cancer Ther. 2018 Aug;17(8):1683-1693. doi: 10.1158/1535-7163.MCT-17-0911., Epub 2018 May 10. PMID:29748212[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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