Document Detail


Inhibition of urease by bismuth(III): implications for the mechanism of action of bismuth drugs.
MedLine Citation:
PMID:  16937256     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (13)C 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.
Authors:
Li Zhang; Scott B Mulrooney; Andy F K Leung; Yibo Zeng; Ben B C Ko; Robert P Hausinger; Hongzhe Sun
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine     Volume:  19     ISSN:  0966-0844     ISO Abbreviation:  Biometals     Publication Date:  2006 Oct 
Date Detail:
Created Date:  2006-08-28     Completed Date:  2007-04-25     Revised Date:  2014-07-09    
Medline Journal Info:
Nlm Unique ID:  9208478     Medline TA:  Biometals     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  503-11     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Anti-Ulcer Agents / therapeutic use
Bacterial Proteins / antagonists & inhibitors,  chemistry,  genetics,  metabolism
Binding Sites
Bismuth / chemistry,  metabolism*,  therapeutic use
Cysteine / metabolism
Helicobacter Infections / drug therapy
Klebsiella / enzymology
Models, Molecular
Molecular Sequence Data
Nuclear Magnetic Resonance, Biomolecular
Plant Proteins / antagonists & inhibitors,  chemistry,  genetics,  metabolism
Protein Conformation
Sequence Alignment
Sulfhydryl Compounds / chemistry
Urease / antagonists & inhibitors*,  chemistry,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
DK45686/DK/NIDDK NIH HHS; R01 DK045686/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Ulcer Agents; 0/Bacterial Proteins; 0/Plant Proteins; 0/Sulfhydryl Compounds; EC 3.5.1.5/Urease; K848JZ4886/Cysteine; U015TT5I8H/Bismuth

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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