Targeting Helicobacter pylori urease activity and maturation: In-cell high-throughput approach for drug discovery

Tarsia, Cinzia; Danielli, Alberto; Florini, Francesca; Cinelli, Paolo; Ciurli, Stefano; Zambelli, Barbara

doi:10.1016/j.bbagen.2018.07.020

Cited by 31 publications

(24 citation statements)

References 58 publications

(67 reference statements)

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“…Urease activity might be modulated by the flbA gene, the same gene that is involved in flagellar biosynthesis [ 29 ]. The inhibition of urease is considered to constitute a potential therapeutic strategy preventing H. pylori -related diseases [ 30 ].…”

Section: Ureasementioning

confidence: 99%

Helicobacter pylori Virulence Factors—Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment

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Sitarz

et al. 2020

Cells

201

163

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Gastric cancer constitutes one of the most prevalent malignancies in both sexes; it is currently the fourth major cause of cancer-related deaths worldwide. The pathogenesis of gastric cancer is associated with the interaction between genetic and environmental factors, among which infection by Helicobacter pylori (H. pylori) is of major importance. The invasion, survival, colonization, and stimulation of further inflammation within the gastric mucosa are possible due to several evasive mechanisms induced by the virulence factors that are expressed by the bacterium. The knowledge concerning the mechanisms of H. pylori pathogenicity is crucial to ameliorate eradication strategies preventing the possible induction of carcinogenesis. This review highlights the current state of knowledge and the most recent findings regarding H. pylori virulence factors and their relationship with gastric premalignant lesions and further carcinogenesis.

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Section: Ureasementioning

confidence: 99%

Helicobacter pylori Virulence Factors—Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment

Baj

Forma

Sitarz

et al. 2020

Cells

201

163

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“…Although previous studies identified several molecules that bind urease and inhibit it competitively or uncompetitively, none of them is generally used in therapy, due to their severe side effects or limited ability to pass the bacterial membrane [ 14 , 15 ]. Recently, an alternative strategy to design urease inhibitors has been proposed by targeting, instead of the enzyme, the process that delivers nickel ions into the enzyme active site, precluding enzyme maturation to the active Ni(II)-loaded urease [ 17 ]. This activation process is governed by the interplay of at least four accessory proteins, named UreD, UreE, UreF, and UreG, coded by genes belonging to a single operon together with the structural genes [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Nickel and GTP Modulate Helicobacter pylori UreG Structural Flexibility

et al. 2020

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UreG is a P-loop GTP hydrolase involved in the maturation of nickel-containing urease, an essential enzyme found in plants, fungi, bacteria, and archaea. This protein couples the hydrolysis of GTP to the delivery of Ni(II) into the active site of apo-urease, interacting with other urease chaperones in a multi-protein complex necessary for enzyme activation. Whereas the conformation of Helicobacter pylori (Hp) UreG was solved by crystallography when it is in complex with two other chaperones, in solution the protein was found in a disordered and flexible form, defining it as an intrinsically disordered enzyme and indicating that the well-folded structure found in the crystal state does not fully reflect the behavior of the protein in solution. Here, isothermal titration calorimetry and site-directed spin labeling coupled to electron paramagnetic spectroscopy were successfully combined to investigate HpUreG structural dynamics in solution and the effect of Ni(II) and GTP on protein mobility. The results demonstrate that, although the protein maintains a flexible behavior in the metal and nucleotide bound forms, concomitant addition of Ni(II) and GTP exerts a structural change through the crosstalk of different protein regions.

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“…Helicobacter pylori is a Gram-negative pathogenic neutralophilic bacterium with a metabolism harmonized for a neutral pH development, but it is adapted to live in the overly acidic gastrointestinal environment (Tarsia et al, 2018). H. pylori genome encodes for αand β-CAs.…”

Section: Helicobacter Pylori and Its Adaptation In The Stomachmentioning

confidence: 99%

Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori

et al. 2021

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Our understanding of the function of bacterial carbonic anhydrases (CAs, EC 4.2.1.1) has increased significantly in the last years. CAs are metalloenzymes able to modulate CO2, HCO3– and H+ concentration through their crucial role in catalysis of reversible CO2 hydration (CO2 + H2O ⇄ HCO3– + H+). In all living organisms, CA activity is linked to physiological processes, such as those related to the transport and supply of CO2 or HCO3–, pH homeostasis, secretion of electrolytes, biosynthetic processes and photosynthesis. These important processes cannot be ensured by the very low rate of the non-catalyzed reaction of CO2 hydration. It has been recently shown that CAs are important biomolecules for many bacteria involved in human infections, such as Vibrio cholerae, Brucella suis, Salmonella enterica, Pseudomonas aeruginosa, and Helicobacter pylori. In these species, CA activity promotes microorganism growth and adaptation in the host, or modulates bacterial toxin production and virulence. In this review, recent literature in this research field and some of the above-mentioned issues are discussed, namely: (i) the implication of CAs from bacterial pathogens in determining the microorganism growth and virulence; (ii) the druggability of these enzymes using classical CA inhibitors (CAIs) of the sulfonamide-type as examples; (iii) the role played by Helicobacter pylori CAs in the acid tolerance/adaptation of the microbe within the human abdomen; (iv) the role of CAs played in the outer membrane vesicles spawned by H. pylori in its planktonic and biofilm phenotypes; (v) the possibility of using H. pylori CAIs in combination with probiotic strains as a novel anti-ulcer treatment approach. The latter approach may represent an innovative and successful strategy to fight gastric infections in the era of increasing resistance of pathogenic bacteria to classical antibiotics.

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Targeting Helicobacter pylori urease activity and maturation: In-cell high-throughput approach for drug discovery

Cited by 31 publications

References 58 publications

Helicobacter pylori Virulence Factors—Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment

Helicobacter pylori Virulence Factors—Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment

Nickel and GTP Modulate Helicobacter pylori UreG Structural Flexibility

Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori

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