Bacterial urease genomes reveal conserved architecture and ancient gene-swapping clues

Urease is one of the most consequential enzymes in the microbial world. By hydrolyzing urea into ammonia and carbon dioxide, it lets bacteria tap a ubiquitous nitrogen source, buffer their internal pH, and colonize environments as disparate as agricultural soils, ocean gyres, ruminant rumens, and the acid-bathed human stomach. Yet most surveys of its distribution across bacteria have leaned on a single marker gene, ureC, which encodes the catalytic subunit and says little about how the surrounding system is actually built. A new comparative phylogenomic study, published in Molecular Genetics and Genomics by Monalisha Pal Sarkar and Ayon Pal of Raiganj University in West Bengal, India, takes a more exhaustive approach and paints a richer picture of how this nickel-dependent machine has been assembled, duplicated, and passed around across the bacterial tree of life.

The researchers assembled a stratified panel of 237 complete bacterial genomes, deliberately chosen to span diverse ecological niches and genome-level characteristics such as size, GC content, and coding capacity. Rather than trusting annotation pipelines alone, they combined annotation-guided screening with profile hidden Markov model searches, a sensitive method for detecting remote protein homologs, and then manually reconstructed each candidate urease locus to confirm its architecture. The panel was then classified into three tiers: genomes with at least one complete urease locus, genomes with candidate but incomplete neighborhoods, and genomes with no supported urease system at all.

The headline numbers are striking in themselves. Of the 237 genomes, 149 encoded at least one complete urease locus, 11 carried candidate but incomplete neighborhoods, and 77 had no detectable urease genes whatsoever. Across the panel, the authors recovered 173 urease-associated genomic neighborhoods. The overwhelming majority, 150 loci, followed the canonical ureABC architecture, in which three structural genes encode the alpha, beta, and gamma subunits that assemble into the active enzyme, typically flanked by accessory genes such as ureD, ureE, ureF, and ureG that shepherd nickel ions into the catalytic center.

Against this conserved backdrop, one alternative design stood out. Seven loci, all confined to Helicobacter, displayed a fused configuration in which the structural genes are arranged as an AB fusion rather than as separate reading frames. This arrangement, best known from the gastric pathogen Helicobacter pylori, persisted in the dataset as a small but stable, lineage-restricted architecture, a reminder that even a deeply conserved enzyme system can tolerate structural tinkering within particular evolutionary branches. Sixteen additional loci were classified as partial or split, highlighting how assembly artifacts, pseudogenization, or genuine decay can blur the boundaries of what counts as a functional urease system.

One of the study’s most intriguing findings concerns genomes that carry two complete canonical urease systems at once. Eight genomes in the panel encoded duplicated loci, and in every case both copies mapped to the same top-level assembly sequence record, ruling out contamination from separate plasmids or unplaced contigs. When the authors compared the two copies within each genome, they found that the paired loci differed in gene order and typically shared only about 62 to 63 percent identity across their concatenated ureABC sequences. That level of divergence is far too deep to reflect a recent, exact duplication. Instead, it points to older internal duplication followed by divergence, or to the secondary acquisition of a second, foreign urease module at some earlier point in the lineage’s history.

To probe how urease systems move across evolutionary distances, the authors built a gene tree from concatenated ureABC sequences and compared it with a genome-wide species tree for the same organisms. If a urease gene tree places a locus next to species that are, by the species tree, only distant relatives, that incongruence is a classic signature of horizontal gene transfer. The comparison flagged 12 candidate incongruent loci, all of them complete canonical systems, marking them as the strongest candidates for intergeneric transfer within the dataset.

Manual inspection of the most compelling examples revealed something ecologically coherent rather than random. Several candidate transfer events clustered in nitrifying bacteria and marine cyanobacteria, two groups for which urea hydrolysis has clear adaptive value: nitrifiers gain a supplemental nitrogen and energy substrate, while ocean-dwelling picocyanobacteria such as Prochlorococcus can exploit urea as a reduced nitrogen source in nutrient-poor waters. In enteric bacteria, the incongruent urease neighborhoods were strikingly associated with nickel transport and hydrogenase-related genes, suggesting that these loci arrived as coordinated functional packages, carrying not just the enzyme but the machinery needed to supply its essential nickel cofactor.

The broader significance of the work lies in its reframing of urease as an evolutionary mosaic. The catalytic core, the ureABC trimer and its nickel metallocenter, is architecturally conserved to a remarkable degree, reflecting the stringent biochemical requirements of activating carbon dioxide and ammonia chemistry with a nickel center. But the surrounding genomic context, including transporters, accessory proteins, and regulatory elements, varies substantially between lineages, tailored to the specific ecological pressures each bacterium faces. The study’s locus-level reconstruction, rather than single-gene screening, is what made this layered picture visible, and the authors argue that future comparative work should treat the entire neighborhood, not just ureC, as the unit of analysis.

The findings also carry practical weight. Urease activity underpins a remarkable range of applications and problems: it drives infection-associated kidney stone formation by Proteus mirabilis, enables H. pylori to survive stomach acid, contributes to ammonia toxicity in ruminant digestion, and powers engineered biomineralization technologies that use ureolytic bacteria to cement sand, seal concrete cracks, and remove heavy metals from water. Understanding which organisms carry which urease architectures, how those systems are regulated by nickel availability, and how readily they move between lineages could sharpen predictions about pathogen virulence, soil nitrogen cycling, and the design of biomineralizing microbial consortia.

As genome databases continue to expand, studies of this kind will only grow more informative. The stratified panel approach used here, combining ecological metadata with rigorous locus reconstruction and species-tree comparison, offers a template for interrogating other multi-gene microbial systems whose distribution may likewise be shaped by a mix of vertical inheritance, duplication, and horizontal exchange. For urease, the message is clear: the enzyme’s blueprint is ancient and shared, but its passport has been stamped many times as it traveled between bacterial genera across evolutionary time.

Subject of Research: Comparative phylogenomics of bacterial urease gene systems across diverse bacterial genomes

Article Title: Comparative phylogenomics of bacterial urease systems reveals architectural conservation, lineage-specific specialization, and candidate horizontal transfer

Article References: Comparative phylogenomics of bacterial urease systems reveals architectural conservation, lineage-specific specialization, and candidate horizontal transfer. (n.d.). https://doi.org/10.1007/s00438-026-02507-y

Image Credits: AI Generated

DOI: 10.1007/s00438-026-02507-y

Keywords: urease, bacteria, phylogenomics, horizontal gene transfer, gene duplication, nickel metalloenzyme, Helicobacter pylori, nitrogen cycling, marine cyanobacteria, nitrifiers, genomics, ureABC