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==Structure of Bifidobacterium dentium beta-glucuronidase complexed with C6-hexyl uronic isofagomine== | ==Structure of Bifidobacterium dentium beta-glucuronidase complexed with C6-hexyl uronic isofagomine== | ||
<StructureSection load='6ld0' size='340' side='right'caption='[[6ld0]]' scene=''> | <StructureSection load='6ld0' size='340' side='right'caption='[[6ld0]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LD0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LD0 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6ld0]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Bifdb Bifdb]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LD0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LD0 FirstGlance]. <br> | ||
</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=6ld0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ld0 OCA], [https://pdbe.org/6ld0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ld0 RCSB], [https://www.ebi.ac.uk/pdbsum/6ld0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ld0 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E8X:(2~{S},3~{S},4~{R},5~{R})-2-hexyl-4,5-bis(oxidanyl)piperidine-3-carboxylic+acid'>E8X</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lacZ1, BDP_2112 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=401473 BIFDB])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Beta-galactosidase Beta-galactosidase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.23 3.2.1.23] </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=6ld0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ld0 OCA], [https://pdbe.org/6ld0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ld0 RCSB], [https://www.ebi.ac.uk/pdbsum/6ld0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ld0 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of beta-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial beta-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 muM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells. | |||
Entropy-driven binding of gut bacterial beta-glucuronidase inhibitors ameliorates irinotecan-induced toxicity.,Lin HY, Chen CY, Lin TC, Yeh LF, Hsieh WC, Gao S, Burnouf PA, Chen BM, Hsieh TJ, Dashnyam P, Kuo YH, Tu Z, Roffler SR, Lin CH Commun Biol. 2021 Mar 4;4(1):280. doi: 10.1038/s42003-021-01815-w. PMID:33664385<ref>PMID:33664385</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6ld0" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Galactosidase 3D structures|Galactosidase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Beta-galactosidase]] | |||
[[Category: Bifdb]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hsieh T | [[Category: Hsieh, T J]] | ||
[[Category: Lin C | [[Category: Lin, C H]] | ||
[[Category: Lin H | [[Category: Lin, H Y]] | ||
[[Category: Carbohydrate]] | |||
[[Category: Complex]] | |||
[[Category: Glycosidase]] | |||
[[Category: Inhibitor]] | |||
Revision as of 09:11, 11 August 2021
Structure of Bifidobacterium dentium beta-glucuronidase complexed with C6-hexyl uronic isofagomineStructure of Bifidobacterium dentium beta-glucuronidase complexed with C6-hexyl uronic isofagomine
Structural highlights
Publication Abstract from PubMedIrinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of beta-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial beta-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (Ki = 0.0045 and 105 muM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells. Entropy-driven binding of gut bacterial beta-glucuronidase inhibitors ameliorates irinotecan-induced toxicity.,Lin HY, Chen CY, Lin TC, Yeh LF, Hsieh WC, Gao S, Burnouf PA, Chen BM, Hsieh TJ, Dashnyam P, Kuo YH, Tu Z, Roffler SR, Lin CH Commun Biol. 2021 Mar 4;4(1):280. doi: 10.1038/s42003-021-01815-w. PMID:33664385[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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