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Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous
bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
,
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
, algae, plants, and some
invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordat ...
, as well as in soils, as a soil enzyme. They are nickel-containing metalloenzymes of high molecular weight. These
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s
catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the hydrolysis of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
into
carbon dioxide Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is trans ...
and
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
: : (NH2)2CO + H2O CO2 + 2NH3 The hydrolysis of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
occurs in two stages. In the first stage,
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
and
carbamic acid Carbamic acid, which might also be called aminoformic acid or aminocarboxylic acid, is the chemical compound with the formula . It can be obtained by the reaction of ammonia and carbon dioxide at very low temperatures, which also yields an equ ...
are produced. The carbamate spontaneously and rapidly hydrolyzes to
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
and carbonic acid. Urease activity increases the pH of its environment as ammonia is produced, which is basic.


History

Its activity was first identified in 1876 by Frédéric Alphonse Musculus as a soluble ferment. In 1926, James B. Sumner, showed that urease is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
by examining its crystallized form. Sumner's work was the first demonstration that a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
can function as an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
and led eventually to the recognition that most enzymes are in fact proteins. Urease was the first enzyme crystallized. For this work, Sumner was awarded the
Nobel prize in chemistry ) , image = Nobel Prize.png , alt = A golden medallion with an embossed image of a bearded man facing left in profile. To the left of the man is the text "ALFR•" then "NOBEL", and on the right, the text (smaller) "NAT•" then "M ...
in 1946. The crystal structure of urease was first solved by P. A. Karplus in 1995.


Structure

A 1984 study focusing on urease from
jack bean ''Canavalia ensiformis'' (jack bean) is a legume which is used for animal fodder and human nutrition, especially in Brazil where it is called ''feijão-de-porco'' ("pig bean"). It is also the source of concanavalin A. Description ''C. ensi ...
found that the active site contains a pair of
nickel Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow ...
centers.
In vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
activation also has been achieved with
manganese Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
and
cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...
in place of nickel. Lead salts are inhibiting. The molecular weight is either 480
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
or 545
kDa The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
for jack-bean urease (calculated mass from the amino acid sequence). 840 amino acids per molecule, of which 90 are cysteine residues. The optimum pH is 7.4 and optimum temperature is 60 °C. Substrates include urea and
hydroxyurea Hydroxycarbamide, also known as hydroxyurea, is a medication used in sickle-cell disease, essential thrombocythemia, chronic myelogenous leukemia, polycythemia vera, and cervical cancer. In sickle-cell disease it increases fetal hemoglobin and d ...
. 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. An exceptional urease is obtained from ''Helicobacter'' sp.. These are composed of two subunits, α(26–31 kDa)-β(61–66 kDa). These subunits form a supramolecular (αβ)12 dodecameric complex. of repeating α-β subunits, each coupled pair of subunits has an active site, for a total of 12 active sites. It plays an essential function for survival, neutralizing gastric acid by allowing
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
to enter into
periplasm The periplasm is a concentrated gel-like matrix in the space between the inner cytoplasmic membrane and the bacterial outer membrane called the ''periplasmic space'' in gram-negative bacteria. Using cryo-electron microscopy it has been found that ...
via a proton-gated urea channel. The presence of urease is used in the diagnosis of ''
Helicobacter ''Helicobacter'' is a genus of Gram-negative bacteria possessing a characteristic helical shape. They were initially considered to be members of the genus ''Campylobacter'', but in 1989, Goodwin ''et al.'' published sufficient reasons to justif ...
'' species. All bacterial ureases are solely cytoplasmic, except for those in ''Helicobacter pylori'', which along with its cytoplasmic activity, has external activity with host cells. In contrast, all plant ureases are cytoplasmic. Fungal and plant ureases are made up of identical subunits (~90 kDa each), most commonly assembled as trimers and hexamers. For example, jack bean urease has two structural and one catalytic subunit. 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. The mass of the
hexamer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relative ...
with the 12 nickel ions is 545.34 kDa. Other examples of homohexameric structures of plant ureases are those of soybean, pigeon pea and cotton seeds enzymes. It is important to note, that although composed of different types of subunits, ureases from different sources extending from bacteria to plants and fungi exhibit high homology of amino acid sequences. The single plant urease chain is equivalent to a fused γ-β-α organization. The ''Helicobacter'' "α" is equivalent to a fusion of the normal bacterial γ-β subunits, while its "β" subunit is equivalent to the normal bacterial α. The three-chain organization is likely ancestral.


Activity

The ''k''cat/''K''m of urease in the processing of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
is 1014 times greater than the rate of the uncatalyzed elimination reaction of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
. There are many reasons for this observation in nature. The proximity of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
to active groups in the active site along with the correct orientation of urea allow hydrolysis to occur rapidly.
Urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
alone is very stable due to the resonance forms it can adopt. The stability of urea is understood to be due to its
resonance Resonance describes the phenomenon of increased amplitude that occurs when the frequency of an applied Periodic function, periodic force (or a Fourier analysis, Fourier component of it) is equal or close to a natural frequency of the system ...
energy, which has been estimated at 30–40 kcal/mol. This is because the
zwitterionic In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively- and negatively-charged functional groups. : With amino acids, for example, in solution a chemical equilibrium wil ...
resonance forms all donate electrons to the
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
carbon making it less of an
electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...
making it less reactive to nucleophilic attack.


Active site

The active site of ureases is located in the α (alpha) subunits. It is a bis-μ-hydroxo dimeric
nickel Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow ...
center, with an interatomic distance of ~3.5 Å. > The Ni(II) pair are weakly antiferromagnetically coupled.
X-ray absorption spectroscopy X-ray absorption spectroscopy (XAS) is a widely used technique for determining the local geometric and/or electronic structure of matter. The experiment is usually performed at synchrotron radiation facilities, which provide intense and tunabl ...
(XAS) studies of '' Canavalia ensiformis'' (jack bean), ''Klebsiella aerogenes'' and ''
Sporosarcina pasteurii ''Sporosarcina pasteurii'' formerly known as ''Bacillus pasteurii'' from older taxonomies, is a gram positive bacterium with the ability to precipitate calcite and solidify sand given a calcium source and urea; through the process of microbiol ...
'' (formerly known as ''Bacillus pasteurii'') confirm 5–6 coordinate nickel ions with exclusively O/N ligation, including two imidazole ligands per nickel. Urea substrate is proposed to displace
aquo ligand In chemistry, metal aquo complexes are coordination compounds containing metal ions with only water as a ligand. These complexes are the predominant species in aqueous solutions of many metal salts, such as metal nitrates, sulfates, and perch ...
s. Water molecules located towards the opening of the active site form a tetrahedral cluster that fills the cavity site through hydrogen bonds. Some amino acid residues are proposed to form mobile flap of the site, which gate for the substrate. Cysteine residues are common in the flap region of the enzymes, which have been determined not to be essential in catalysis, although involved in positioning other key residues in the active site appropriately. In ''
Sporosarcina pasteurii ''Sporosarcina pasteurii'' formerly known as ''Bacillus pasteurii'' from older taxonomies, is a gram positive bacterium with the ability to precipitate calcite and solidify sand given a calcium source and urea; through the process of microbiol ...
'' urease, the flap was found in the open conformation, while its closed conformation is apparently needed for the reaction. When compared, the α subunits of ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is thoug ...
'' urease and other bacterial ureases align with the jack bean ureases. The binding of urea to the active site of urease has not been observed.


Proposed mechanisms


Blakeley/Zerner

One mechanism for the catalysis of this reaction by urease was proposed by Blakely and Zerner. It begins with a nucleophilic attack by the
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
oxygen of the
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
molecule onto the 5-coordinate Ni (Ni-1). A weakly coordinated water ligand is displaced in its place. A lone pair of electrons from one of the nitrogen atoms on the
Urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
molecule creates a double bond with the central carbon, and the resulting NH2 of the coordinated substrate interacts with a nearby positively charged group. Blakeley and Zerner proposed this nearby group to be a Carboxylate ion, although deprotonated carboxylates are negatively charged. A hydroxide ligand on the six coordinate Ni is deprotonated by a base. The carbonyl carbon is subsequently attacked by the electronegative oxygen. 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. The breakdown of this intermediate is then helped by a sulfhydryl group of a cysteine located near the active site. A hydrogen bonds to one of the nitrogen atoms, breaking its bond with carbon, and releasing an molecule. Simultaneously, the bond between the oxygen and the 6-coordinate nickel is broken. This leaves a carbamate ion coordinated to the 5-coordinate Ni, which is then displaced by a water molecule, regenerating the enzyme. The carbamate produced then spontaneously degrades to produce another ammonia and carbonic acid.


Hausinger/Karplus

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. 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. In addition, the general acidic ligand required to protonate the urea nitrogen was not identified. Hausinger and Karplus suggests a reverse protonation scheme, where a protonated form of the His320 ligand plays the role of the general acid and the Ni2-bound water is already in the deprotonated state. 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. While the majority of the His320 ligands and bound water will not be in their active forms (protonated and deprotonated, respectively,) it was calculated that approximately 0.3% of total urease enzyme would be active at any one time. 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. Placing the His320 ligand as an essential component in the mechanism also takes into account the mobile flap region of the enzyme. As this histidine ligand is part of the mobile flap, binding of the urea substrate for catalysis closes this flap over the active site and with the addition of the hydrogen bonding pattern to urea from other ligands in the pocket, speaks to the selectivity of the urease enzyme for urea.


Ciurli/Mangani

The mechanism proposed by Ciurli and Mangani is one of the more recent and currently accepted views of the mechanism of urease and is based primarily on the different roles of the two
nickel Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow ...
ions in the active site. One of which binds and activates urea, the other nickel ion binds and activates the nucleophilic water molecule. With regards to this proposal, urea enters the active site cavity when the mobile ‘flap’ (which allows for the entrance of urea into the active site) is open. Stability of the binding of urea to the active site is achieved via a
hydrogen-bonding In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a l ...
network, orienting the substrate into the catalytic cavity. Urea binds to the five-coordinated nickel (Ni1) with the carbonyl
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
atom. It approaches the six-coordinated nickel (Ni2) with one of its amino groups and subsequently bridges the two nickel centers. The binding of the urea carbonyl oxygen atom to Ni1 is stabilized through the protonation state of Hisα222 Nԑ. 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. The Alaα170 and Alaα366 are now oriented in a way that their carbonyl groups act as hydrogen-bond acceptors towards NH2 group of urea, thus aiding its binding to Ni2. Urea is a very poor chelating ligand due to low Lewis base character of its NH2 groups. However the carbonyl oxygens of Alaα170 and Alaα366 enhance the basicity of the NH2 groups and allow for binding to Ni2. Therefore, in this proposed mechanism, the positioning of urea in the active site is induced by the structural features of the active site residues which are positioned to act as hydrogen-bond donors in the vicinity of Ni1 and as acceptors in the vicinity of Ni2. The main structural difference between the Ciurli/Mangani mechanism and the other two is that it incorporates a
nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
, oxygen bridging urea that is attacked by a bridging hydroxide.


Action in pathogenesis

Bacterial ureases are often the mode of
pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
for many medical conditions. They are associated with
hepatic encephalopathy Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stage ...
/ Hepatic coma, infection stones, and peptic ulceration.


Infection stones

Infection induced urinary stones are a mixture of struvite (MgNH4PO4•6H2O) and carbonate apatite a10(PO4)6•CO3 These polyvalent ions are soluble but become insoluble when
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
is produced from microbial urease during
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
hydrolysis, as this increases the surrounding environments pH from roughly 6.5 to 9. The resultant alkalinization results in stone crystallization. In humans the microbial urease, ''Proteus mirabilis'', is the most common in infection induced urinary stones.


Urease in hepatic encephalopathy / hepatic coma

Studies have shown that ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is thoug ...
'' along with
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...
of the liver cause
hepatic encephalopathy Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stage ...
and hepatic coma. ''Helicobacter pylori'' release microbial ureases into the stomach. The urease hydrolyzes
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
to produce
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
and carbonic acid. As the bacteria are localized to the stomach
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
produced is readily taken up by the
circulatory system The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
from the gastric lumen. This results in elevated
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
levels in the blood, a condition known as hyperammonemia; eradication of ''Helicobacter pylori'' show marked decreases in
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
levels.


Urease in peptic ulcers

''Helicobacter pylori'' is also the cause of peptic ulcers with its manifestation in 55–68% reported cases. This was confirmed by decreased
ulcer An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing o ...
bleeding and
ulcer An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing o ...
reoccurrence after eradication of the
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
. In the stomach there is an increase in pH of the mucosal lining as a result of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important ...
hydrolysis, which prevents movement of
hydrogen ions A hydrogen ion is created when a hydrogen atom loses or gains an electron. A positively charged hydrogen ion (or proton) can readily combine with other particles and therefore is only seen isolated when it is in a gaseous state or a nearly particle ...
between gastric glands and gastric lumen. In addition, the high
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
concentrations have an effect on intercellular
tight junctions Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein junctional complexes whose canonical function is to prevent leakage of solutes and water and seals between the epith ...
increasing permeability and also disrupting the gastric
mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It i ...
of the stomach.


Occurrence and applications in agriculture

Urea is found naturally in the environment and is also artificially introduced, comprising more than half of all synthetic nitrogen fertilizers used globally. Heavy use of urea is thought to promote eutrophication, despite the observation that urea is rapidly transformed by microbial ureases, and thus usually does not persist. Environmental urease activity is often measured as an indicator of the health of microbial communities. 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.


Inhibition in fertilizers

The inhibition of urease is a significant goal in agriculture because the rapid breakdown of urea-based fertilizers is wasteful and environmentally damaging. Phenyl phosphorodiamidate and N-(n-butyl)thiophosphoric triamide are two such inhibitors.


Biomineralization

By promoting the formation of calcium carbonate, ureases are potentially useful for
biomineralization Biomineralization, also written biomineralisation, is the process by which living organisms produce minerals, often to harden or stiffen existing tissues. Such tissues are called mineralized tissues. It is an extremely widespread phenomenon; ...
-inspired processes. Notably, micro-biologically induced formation of calcium carbonate can be used in making bioconcrete.


Non-enzymatic action

In addition to acting as an enzyme, some ureases (especially plant ones) have additional effects that persist even when the catalytic function is disabled. These include entomotoxicity, inhibition of fungi, neurotoxicity in mammals, promotion of endocytosis and inflammatory eicosanoid production in mammals, and induction of chemotaxis in bacteria. These activities may be part of a defense mechanism. Urease insect-toxicity was originally noted in canatoxin, an orthologous isoform of jack bean urease. Digestion of the peptide identified a 10-kDa portion most responsible for this effect, termed jaburetox. An analogous portion from the soybean urease is named soyuretox. Studies on insects show that the entire protein is toxic without needing any digestion, however. Nevertheless, the "uretox" peptides, being more concentrated in toxicity, show promise as
biopesticide A Biopesticide is a biological substance or organism that damages, kills, or repels organisms seens as pests. Biological pest management intervention involves predatory, parasitic, or chemical relationships. They are obtained from organisms inclu ...
s.


As diagnostic test

Many gastrointestinal or urinary tract pathogens produce urease, enabling the detection of urease to be used as a diagnostic to detect presence of pathogens. Urease-positive pathogens include: *'' Proteus mirabilis'' and '' Proteus vulgaris'' *'' Ureaplasma urealyticum'', a relative of '' Mycoplasma'' spp. *'' Nocardia'' *'' Corynebacterium urealyticum'' *''
Cryptococcus ''Cryptococcus'' is a genus of fungi in the family Cryptococcaceae that includes both yeasts and filamentous species. The filamentous, sexual forms or teleomorphs were formerly classified in the genus ''Filobasidiella'', while ''Cryptococcus'' ...
'' spp., an
opportunistic Opportunism is the practice of taking advantage of circumstances – with little regard for principles or with what the consequences are for others. Opportunist actions are expedient actions guided primarily by self-interested motives. The term ...
fungus *''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is thoug ...
'' *Certain
Enteric bacteria Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut mi ...
including '' Proteus'' spp., '' Klebsiella'' spp., '' Morganella'', '' Providencia'', and possibly ''
Serratia ''Serratia'' is a genus of Gram-negative, facultatively anaerobic, rod-shaped bacteria of the family Yersiniaceae. According to the List of Prokaryotic names with Standing Nomenclature (LPSN), there are currently 19 species of ''Serratia'' that a ...
'' spp. *''
Brucella ''Brucella'' is a genus of Gram-negative bacteria, named after David Bruce (1855–1931). They are small (0.5 to 0.7 by 0.6 to 1.5 µm), non encapsulated, non motile, facultatively intracellular coccobacilli. ''Brucella'' spp. are the caus ...
'' * '' Staphylococcus saprophyticus'' * '' Staphylococcus aureus''


Ligands


Inhibitors

A wide range of urease inhibitors of different structural families are known. Inhibition of urease is not only of interest to agriculture, but also to medicine as pathogens like ''
H. pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is thoug ...
'' produce urease as a survival mechanism. Known structural classes of inhibitors include: * Analogues of urea, the strongest being
thiourea Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), except that the oxygen atom is replaced by a sulfur atom (as implied by the ''thio-'' prefix); however, the properties of urea a ...
s like 1-(4-chlorophenyl)-3-palmitoylthiourea. * Phosphoramidates, the most commonly used in agriculture (see above). * Hydroquinone and quinones. In medicine, the most interesting are quinolones, already a class of widely used antibiotics. * Some plant metabolites are also urease inhibitors, an example being allicin. These have potential both as environmentally-friendly fertilizer additives and natural drugs.


Extraction

First isolated as a crystal in 1926 by Sumner, using acetone solvation and centrifuging. Modern biochemistry has increased its demand for urease. Jack bean meal, watermelon seeds, and pea seeds have all proven useful sources of urease.


See also

* Urea carboxylase * Allophanate hydrolase * Urease test


References


External links

* {{Authority control Nickel enzymes EC 3.5.1