Urease

Mazzei, Luca; Ciurli, Stefano

doi:10.1002/9781119951438.eibc2776

Cited by 4 publications

(3 citation statements)

References 129 publications

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“…The quest for novel urease inhibitors is thus central to various fields 36,37 and several compounds have been found to inhibit urease. 7,38–56 Another strategy to inhibit urease is the use of coordination polymers (CPs) and complexes, 57,58 formed by the self-assembly of metal ions and organic ligands and representing one of the most prolific research areas of crystal engineering and medicinal inorganic chemistry in the last 15 years. Interest in such compounds comes from their double organic–inorganic nature and the possibility of simultaneously exhibiting the properties of both classes.…”

Section: Introductionmentioning

confidence: 99%

Is bismuth(iii) able to inhibit the activity of urease? Puzzling results in the quest for soluble urease complexes for agrochemical and medicinal applications

Contini,

Paul,

Mazzei

et al. 2024

Dalton Trans.

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Section: Introductionmentioning

confidence: 99%

Is bismuth(iii) able to inhibit the activity of urease? Puzzling results in the quest for soluble urease complexes for agrochemical and medicinal applications

Contini,

Paul,

Mazzei

et al. 2024

Dalton Trans.

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“…Therefore, urease represents a target to develop antibiotics for infections by ureolytic bacteria. The activity of urease relies on the presence of an active site containing two Ni(II) ions bridged by the carboxylate group of a carbamylated lysine and by a hydroxide ion, the nucleophile of the hydrolysis reaction (Mazzei et al, 2020;Mazzei and Ciurli, 2021). While several enzyme inhibitors that target the catalytic mechanism have been proposed to this task, the enzyme activation process could be another way to modulate its activity.…”

Section: Introductionmentioning

confidence: 99%

Functional contacts for activation of urease from Helicobacter pylori: an integrated approach using evolutionary couplings, in-cell enzymatic assays, and computational docking

Carosella,

Brock,

Zambelli

et al. 2023

Front. Chem. Biol.

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Introduction: Urease is an enzyme exploited by many virulent bacteria and fungi to infect the host and exert their virulence. The Gram-negative bacterium Helicobacter pylori relies on the activity of urease to infect the highly acidic human stomach. The activity of urease depends on the presence of a catalytic site containing two Ni(II) ions. In vivo, urease is initially synthesized as an inactive apo-enzyme and requires a post-translational activation process that involves the incorporation of the metal ions into its buried active site. In H. pylori, as well as in other bacteria, this activation process is mediated by four accessory proteins, named UreD, UreF, UreG, and UreE. Targeting the interactions between urease chaperones could potentially inhibit the activation of urease through blocking the Ni(II) ions incorporation, providing a route for the development of antimicrobial strategies against ureolytic pathogens.Methods: In this paper, an evolutionary couplings (EC) approach was adopted to determine the interaction surface between urease and UreD, the first protein that binds the enzyme, preparing it for the subsequent activation steps. Site-directed mutagenesis and an in-cell assay were used to detect urease activity in recombinant bacteria expressing the mutated operon. The obtained data were used to drive a protein-protein docking computational approach.Results and Discussion: The EC prediction retrieved ten pairs of residues lying at the interface between UreD and the urease subunit UreB, likely involved in contacts essential to build the protein complex. These contacts were largely confirmed experimentally, leading to the obtainment of a model for the urease-UreD complex that agrees well with the recently reported experimental cryo-EM structure. This work represents a proof of concept for the calculation of reliable models of protein interaction surfaces in the absence of experimental structures of critical assemblies.

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“…Even though a broad family of urease inhibitors which directly bind to the Ni II ions in the active site has been characterized in the past decades,[ 16c , 18c ] an ever‐growing number of ligands are emerging that share with p ‐BQ the ability of inactivating urease by blocking the mobility of the active site flap, including, among the others, catechol (CAT) [26] and its derivatives, [27] as well as heavy transition metal ions, such as silver(I) [28] and gold(I). [29] Considering that p ‐BQ has been also reported to inhibit intracellular urease in in vivo experiments, [30] and given the presence, in the living cells, of a reducing environment that would facilitate the presence of HQs in their fully reduced form, the aim of the present work has been to provide a molecular characterization for the inhibition of urease by HQ, comparing the obtained results with the reported data for the inhibition of oxidized p ‐BQ on the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Urease by Hydroquinones: A Structural and Kinetic Study

Mazzei

Cianci

Ciurli

2022

Chemistry A European J

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Hydroquinones are a class of organic compounds abundant in nature that result from the full reduction of the corresponding quinones. Quinones are known to efficiently inhibit urease, a Ni II -containing enzyme that catalyzes the hydrolysis of urea to yield ammonia and carbonate and acts as a virulence factor of several human pathogens, in addition to decreasing the efficiency of soil organic nitrogen fertilization. Here, we report the molecular characterization of the inhibition of urease from Sporosarcina pasteurii (SPU) and Canavalia ensiformis (jack bean, JBU) by 1,4-hydroquinone (HQ) and its methyl and tert-butyl derivatives. The 1.63-Å resolution X-ray crystal structure of the SPU-HQ complex discloses that HQ covalently binds to the thiol group of αCys322, a key residue located on a mobile protein flap directly involved in the catalytic mechanism. Inhibition kinetic data obtained for the three compounds on JBU reveals the occurrence of an irreversible inactivation process that involves a radical-based autocatalytic mechanism.

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Urease

Cited by 4 publications

References 129 publications

Is bismuth(iii) able to inhibit the activity of urease? Puzzling results in the quest for soluble urease complexes for agrochemical and medicinal applications

Is bismuth(iii) able to inhibit the activity of urease? Puzzling results in the quest for soluble urease complexes for agrochemical and medicinal applications

Functional contacts for activation of urease from Helicobacter pylori: an integrated approach using evolutionary couplings, in-cell enzymatic assays, and computational docking

Inhibition of Urease by Hydroquinones: A Structural and Kinetic Study

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