[5] Urease is important because of its role in the Nitrogen cycle as a key catalyst in the reaction converting urea to ammonium and CO2.

[7] A 1984 study focusing on urease from jack bean found that the active site contains a pair of nickel centers.

Bacterial ureases are composed of three distinct subunits, one large catalytic (α 60–76kDa) and two small (β 8–21 kDa, γ 6–14 kDa) commonly forming (αβγ)3 trimers stoichiometry with a 2-fold symmetric structure (note that the image above gives the structure of the asymmetric unit, one-third of the true biological assembly), they are cysteine-rich enzymes, resulting in the enzyme molar masses between 190 and 300kDa.

[10] Fungal and plant ureases are made up of identical subunits (~90 kDa each), most commonly assembled as trimers and hexamers.

The α subunit contains the active site, it is composed of 840 amino acids per molecule (90 cysteines), its molecular mass without Ni(II) ions amounting to 90.77 kDa.

Other examples of homohexameric structures of plant ureases are those of soybean, pigeon pea and cotton seeds enzymes.

[14] X-ray absorption spectroscopy (XAS) studies of Canavalia ensiformis (jack bean), Klebsiella aerogenes and Sporosarcina pasteurii (formerly known as Bacillus pasteurii)[15] confirm 5–6 coordinate nickel ions with exclusively O/N ligation, including two imidazole ligands per nickel.

A lone pair of electrons from one of the nitrogen atoms on the Urea molecule creates a double bond with the central carbon, and the resulting NH2− of the coordinated substrate interacts with a nearby positively charged group.

A pair of electrons from the nitrogen-carbon double bond returns to the nitrogen and neutralizes the charge on it, while the now 4-coordinate carbon assumes an intermediate tetrahedral orientation.

This leaves a carbamate ion coordinated to the 5-coordinate Ni, which is then displaced by a water molecule, regenerating the enzyme.

[18] The mechanism proposed by Hausinger and Karplus attempts to revise some of the issues apparent in the Blakely and Zerner pathway, and focuses on the positions of the side chains making up the urea-binding pocket.

[5] From the crystal structures from K. aerogenes urease, it was argued that the general base used in the Blakely mechanism, His320, was too far away from the Ni2-bound water to deprotonate in order to form the attacking hydroxide moiety.

[5] The mechanism follows the same path, with the general base omitted (as there is no more need for it) and His320 donating its proton to form the ammonia molecule, which is then released from the enzyme.

[5] While logically, this would imply that the enzyme is not very efficient, contrary to established knowledge, usage of the reverse protonation scheme provides an advantage in increased reactivity for the active form, balancing out the disadvantage.

[5] Placing the His320 ligand as an essential component in the mechanism also takes into account the mobile flap region of the enzyme.

Stability of the binding of urea to the active site is achieved via a hydrogen-bonding network, orienting the substrate into the catalytic cavity.

Additionally, the conformational change from the open to closed state of the mobile flap generates a rearrangement of Alaα222 carbonyl group in such a way that its oxygen atom points to Ni2.

[21] These polyvalent ions are soluble but become insoluble when ammonia is produced from microbial urease during urea hydrolysis, as this increases the surrounding environments pH from roughly 6.5 to 9.

[21] In humans the microbial urease, Proteus mirabilis, is the most common in infection induced urinary stones.

As the bacteria are localized to the stomach ammonia produced is readily taken up by the circulatory system from the gastric lumen.

[21] In addition, the high ammonia concentrations have an effect on intercellular tight junctions increasing permeability and also disrupting the gastric mucous membrane of the stomach.

[21][25] Urea is found naturally in the environment and is also artificially introduced, comprising more than half of all synthetic nitrogen fertilizers used globally.

In the absence of plants, urease activity in soil is generally attributed to heterotrophic microorganisms, although it has been demonstrated that some chemoautotrophic ammonium oxidizing bacteria are capable of growth on urea as a sole source of carbon, nitrogen, and energy.

[28] The inhibition of urease is a significant goal in agriculture because the rapid breakdown of urea-based fertilizers is wasteful and environmentally damaging.

Urease-positive pathogens include: A wide range of urease inhibitors of different structural families are known.

Known structural classes of inhibitors include:[34][35] First isolated as a crystal in 1926 by Sumner, using acetone solvation and centrifuging.