Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs
Bismuth compounds are widely used for the treatment of peptic ulcers and Helicobacter pylori infections. It has been suggested that enzyme inhibition plays an important role in the antibacterial activity of bismuth towards this bacterium. Urease, an enzyme that converts urea into ammonia and carboni...
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Springer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0966-0844
2006
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Online Access: | https://doi.org/10.1007/s10534-005-5449-0 http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0966-0844&volume=19&spage=503&epage=511&date=2006&atitle=Inhibition+of+urease+by+bismuth(III):+Implications+for+the+mechanism+of+action+of+bismuth+drugs http://hdl.handle.net/10722/68784 |
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ftunivhongkonghu:oai:hub.hku.hk:10722/68784 2023-05-15T15:52:55+02:00 Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs Mulrooney, SB Leung, AFK Zeng, Y Sun, H Hausinger, RP Ko, BBC Zhang, L 2006 https://doi.org/10.1007/s10534-005-5449-0 http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0966-0844&volume=19&spage=503&epage=511&date=2006&atitle=Inhibition+of+urease+by+bismuth(III):+Implications+for+the+mechanism+of+action+of+bismuth+drugs http://hdl.handle.net/10722/68784 eng eng Springer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0966-0844 United States BioMetals http://www.scopus.com/mlt/select.url?eid=2-s2.0-33747885475&selection=ref&src=s&origin=recordpage Biometals, 2006, v. 19 n. 5, p. 503-511 doi:10.1007/s10534-005-5449-0 511 121166 WOS:000240098000006 0966-0844 5 http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0966-0844&volume=19&spage=503&epage=511&date=2006&atitle=Inhibition+of+urease+by+bismuth(III):+Implications+for+the+mechanism+of+action+of+bismuth+drugs 16937256 eid_2-s2.0-33747885475 503 http://hdl.handle.net/10722/68784 19 Urease Nuclear magnetic resonance spectroscopy Bismuth Inhibition UV-vis spectroscopy Article 2006 ftunivhongkonghu https://doi.org/10.1007/s10534-005-5449-0 2023-01-14T15:13:31Z Bismuth compounds are widely used for the treatment of peptic ulcers and Helicobacter pylori infections. It has been suggested that enzyme inhibition plays an important role in the antibacterial activity of bismuth towards this bacterium. Urease, an enzyme that converts urea into ammonia and carbonic acid, is crucial for colonization of the acidic environment of the stomach by H. pylori. Here, we show that three bismuth complexes exhibit distinct mechanisms of urease inhibition, with some differences dependent on the source of the enzyme. Bi(EDTA) and Bi(Cys) 3 are competitive inhibitors of jack bean urease with K i values of 1.74 ± 0.14 and 1.84 ± 0.15 mM, while the anti-ulcer drug, ranitidine bismuth citrate (RBC) is a non-competitive inhibitor with a K i value of 1.17 ± 0.09 mM. A 13C NMR study showed that Bi(Cys) 3 reacts with jack bean urease during a 30 min incubation, releasing free cysteines from the metal complex. Upon incubation with Bi(EDTA) and RBC, the number of accessible cysteine residues in the homohexameric plant enzyme decreased by 5.80 ± 0.17 and 11.94 ± 0.13, respectively, after 3 h of reaction with dithiobis(2-nitrobenzoic acid). Kinetic analysis showed that Bi(EDTA) is both a competitive inhibitor and a time-dependent inactivator of the recombinant Klebsiella aerogenes urease. The active C319A mutant of the bacterial enzyme displays a significantly reduced sensitivity toward inactivation by Bi(EDTA) compared with the wild-type enzyme, consistent with binding of Bi 3+ to the active site cysteine (Cys 319) as the mechanism of enzyme inactivation. © Springer 2006. link_to_subscribed_fulltext Article in Journal/Newspaper Carbonic acid University of Hong Kong: HKU Scholars Hub BioMetals 19 5 503 511 |
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Open Polar |
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University of Hong Kong: HKU Scholars Hub |
op_collection_id |
ftunivhongkonghu |
language |
English |
topic |
Urease Nuclear magnetic resonance spectroscopy Bismuth Inhibition UV-vis spectroscopy |
spellingShingle |
Urease Nuclear magnetic resonance spectroscopy Bismuth Inhibition UV-vis spectroscopy Mulrooney, SB Leung, AFK Zeng, Y Sun, H Hausinger, RP Ko, BBC Zhang, L Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs |
topic_facet |
Urease Nuclear magnetic resonance spectroscopy Bismuth Inhibition UV-vis spectroscopy |
description |
Bismuth compounds are widely used for the treatment of peptic ulcers and Helicobacter pylori infections. It has been suggested that enzyme inhibition plays an important role in the antibacterial activity of bismuth towards this bacterium. Urease, an enzyme that converts urea into ammonia and carbonic acid, is crucial for colonization of the acidic environment of the stomach by H. pylori. Here, we show that three bismuth complexes exhibit distinct mechanisms of urease inhibition, with some differences dependent on the source of the enzyme. Bi(EDTA) and Bi(Cys) 3 are competitive inhibitors of jack bean urease with K i values of 1.74 ± 0.14 and 1.84 ± 0.15 mM, while the anti-ulcer drug, ranitidine bismuth citrate (RBC) is a non-competitive inhibitor with a K i value of 1.17 ± 0.09 mM. A 13C NMR study showed that Bi(Cys) 3 reacts with jack bean urease during a 30 min incubation, releasing free cysteines from the metal complex. Upon incubation with Bi(EDTA) and RBC, the number of accessible cysteine residues in the homohexameric plant enzyme decreased by 5.80 ± 0.17 and 11.94 ± 0.13, respectively, after 3 h of reaction with dithiobis(2-nitrobenzoic acid). Kinetic analysis showed that Bi(EDTA) is both a competitive inhibitor and a time-dependent inactivator of the recombinant Klebsiella aerogenes urease. The active C319A mutant of the bacterial enzyme displays a significantly reduced sensitivity toward inactivation by Bi(EDTA) compared with the wild-type enzyme, consistent with binding of Bi 3+ to the active site cysteine (Cys 319) as the mechanism of enzyme inactivation. © Springer 2006. link_to_subscribed_fulltext |
format |
Article in Journal/Newspaper |
author |
Mulrooney, SB Leung, AFK Zeng, Y Sun, H Hausinger, RP Ko, BBC Zhang, L |
author_facet |
Mulrooney, SB Leung, AFK Zeng, Y Sun, H Hausinger, RP Ko, BBC Zhang, L |
author_sort |
Mulrooney, SB |
title |
Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs |
title_short |
Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs |
title_full |
Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs |
title_fullStr |
Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs |
title_full_unstemmed |
Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs |
title_sort |
inhibition of urease by bismuth(iii): implications for the mechanism of action of bismuth drugs |
publisher |
Springer New York LLC. The Journal's web site is located at http://springerlink.metapress.com/openurl.asp?genre=journal&issn=0966-0844 |
publishDate |
2006 |
url |
https://doi.org/10.1007/s10534-005-5449-0 http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0966-0844&volume=19&spage=503&epage=511&date=2006&atitle=Inhibition+of+urease+by+bismuth(III):+Implications+for+the+mechanism+of+action+of+bismuth+drugs http://hdl.handle.net/10722/68784 |
genre |
Carbonic acid |
genre_facet |
Carbonic acid |
op_relation |
BioMetals http://www.scopus.com/mlt/select.url?eid=2-s2.0-33747885475&selection=ref&src=s&origin=recordpage Biometals, 2006, v. 19 n. 5, p. 503-511 doi:10.1007/s10534-005-5449-0 511 121166 WOS:000240098000006 0966-0844 5 http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0966-0844&volume=19&spage=503&epage=511&date=2006&atitle=Inhibition+of+urease+by+bismuth(III):+Implications+for+the+mechanism+of+action+of+bismuth+drugs 16937256 eid_2-s2.0-33747885475 503 http://hdl.handle.net/10722/68784 19 |
op_doi |
https://doi.org/10.1007/s10534-005-5449-0 |
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BioMetals |
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19 |
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