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Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs

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Abstract

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 Bi3+ to the active site cysteine (Cys319) as the mechanism of enzyme inactivation.

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Authors and Affiliations

  1. Department of Chemistry and Open Laboratory of Chemical Biology, The University of Hong Kong, Pokfulam, Hong Kong, P.R. China

    Li Zhang, Andy F. K. Leung, Yibo Zeng, Ben B. C. Ko & Hongzhe Sun

  2. Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, 48824-4320, USA

    Scott B. Mulrooney & Robert P. Hausinger

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  1. Li Zhang
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  2. Scott B. Mulrooney
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  3. Andy F. K. Leung
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  4. Yibo Zeng
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  5. Ben B. C. Ko
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  6. Robert P. Hausinger
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  7. Hongzhe Sun
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Correspondence to Robert P. Hausinger or Hongzhe Sun.

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Zhang, L., Mulrooney, S.B., Leung, A.F.K. et al. Inhibition of urease by bismuth(III): Implications for the mechanism of action of bismuth drugs. Biometals 19, 503–511 (2006). https://doi.org/10.1007/s10534-005-5449-0

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