Ureases: Historical aspects, catalytic, and non-catalytic properties – A review Original paper

What was reviewed?

This review comprehensively examines the enzyme urease, focusing on both its classical catalytic activity—urea hydrolysis into ammonia and carbamate—and its lesser-known non-enzymatic biological roles. Historically significant as the first enzyme ever crystallized and the first protein shown to require nickel as a cofactor, urease has since been implicated in a wide range of biological processes, spanning nitrogen metabolism, virulence in microbial pathogenesis, plant defense, neurotoxicity, and bioinsecticidal activity. The paper delves into the structural, kinetic, and molecular properties of ureases, including their activation mechanisms involving nickel insertion, their evolutionary divergence among taxa, and the role of accessory proteins (e.g., UreD, UreF, UreG, UreE) in catalytic site maturation. Importantly, the review explores biological functions of ureases unrelated to ureolytic activity, such as immunomodulation, platelet aggregation, neurotoxicity, and membrane-disruptive activities, often mediated by urease-derived peptides like jaburetox.

In addition, the review provides a detailed classification and discussion of urease inhibitors, such as hydroxamic acids, polyphenols, quinones, and heavy metals, many of which act through nickel chelation or active site disruption.

Class of Inhibitor	Mechanism of Action
Hydroxamic Acids	Slow-binding inhibitor; interacts with Ni ions in active site;(e.g., Acetohydroxamic Acid)
Phosphorus Compounds	Binds to Ni ions; generates diamidophosphate post-hydrolysis; (e.g., Phosphoramidates)
Polyphenols	Forms metal complexes or oxidized quinones modify thiols;(e.g., Catechol)
Heavy Metals	Inactivates urease by binding to cysteine residues in mobile flap; (e.g., Bi3+, Cu2+)
Quinones	Covalent modification of cysteine in mobile flap; thiol oxidation; (e.g., Benzoquinone)

Who was reviewed?

This review encompasses a broad range of urease-producing organisms, including bacteria (e.g., Helicobacter pylori, Proteus mirabilis, Klebsiella pneumoniae, Cryptococcus neoformans), fungi, and plants (e.g., Canavalia ensiformis, Glycine max), with structural and functional insights derived from both natural and recombinant sources. The microbial taxa included are of special clinical interest due to their virulence mechanisms tied to urease activity or urease-derived functions. Data from both in vivo and in vitro experimental systems are integrated.

Most Important Findings

The review reveals that urease functions extend far beyond ammonia production via urea hydrolysis. Ureases are nickel-dependent metalloenzymes whose virulence-related capabilities involve both their enzymatic activity and structurally embedded, ureolysis-independent functions. These include pro-inflammatory signaling, platelet activation, immunomodulation, and neurotoxicity. Particularly in H. pylori, urease subunits (e.g., UreA and UreB) interact with host receptors such as CD74 to induce cytokine production (e.g., IL-8) and modulate immune responses. Insects and fungi are also affected by urease toxicity via peptides like jaburetox and soyuretox, which exhibit ion channel activity, membrane perturbation, and intracellular signaling effects. These activities are critical for the entomotoxic and antifungal properties observed in plant defense mechanisms.

From a microbiome standpoint, urease-positive pathogens are commonly enriched in dysbiotic states. Major pathogens with urease activity include H. pylori,P. mirabilis, K. pneumoniae, and C. neoformans, among others. Urease contributes to microbial survival in hostile pH environments, formation of urinary and gastric calculi, and systemic hyperammonemia, thereby modulating host-microbiota interactions in both the gut and urogenital tract. Notably, the review underscores the therapeutic potential of targeting urease pathways—including both enzymatic and structural features—for conditions such as hepatic encephalopathy, urinary tract infections, and H. pylori-associated diseases.

Greatest Implications

This review reframes urease as a multifunctional protein, positioning it as both a microbial virulence determinant and a target for pharmacological and agricultural interventions. Clinically, its role in pathogenesis via ammonia production and non-catalytic interactions implicates it in systemic diseases far beyond local infections, including cardiovascular and neurological disorders. For microbiome-targeted medicine, understanding urease as a functional trait rather than a taxonomic marker offers a mechanistic basis for identifying Major Microbial Associations (MMAs) and designing microbiome-targeted interventions (MBTIs), such as nickel chelators (lactoferrin, dimethylglyoxime (DMG), or a Low-Nickel Diet (LNiD). The dual catalytic and non-catalytic activities of urease also suggest the need for multi-modal inhibition strategies. In agriculture, urease-derived peptides could support biocontrol applications, while urease overexpression or peptide transgenesis could bolster crop resistance to pests and fungal pathogens.