Urease

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Urease 2KAU.png
3D model of urease from Klebsiella aerogenes, two Ni2+-ions are shown as green spheres. [1]
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EC no. 3.5.1.5
CAS no. 9002-13-5
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Ureases (EC 3.5.1.5), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. [2] Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-containing metalloenzymes of high molecular weight. [3]

Contents

These enzymes catalyze the hydrolysis of urea into carbon dioxide and ammonia:

(NH2)2CO + H2O urease→ CO2 + 2NH3

The hydrolysis of urea occurs in two stages. In the first stage, ammonia and carbamic acid are produced. The carbamate spontaneously and rapidly hydrolyzes to ammonia 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. [4] In 1926, James B. Sumner, showed that urease is a protein by examining its crystallized form. [5] Sumner's work was the first demonstration that a protein can function as an enzyme 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 in 1946. [6] The crystal structure of urease was first solved by P. A. Karplus in 1995. [5]

Structure

A 1984 study focusing on urease from jack bean found that the active site contains a pair of nickel centers. [7] In vitro activation also has been achieved with manganese and cobalt in place of nickel. [8] Lead salts are inhibiting.

The molecular weight is either 480 kDa or 545 kDa for jack-bean urease (calculated mass from the amino acid sequence). 840 amino acids per molecule, of which 90 are cysteine residues. [9]

The optimum pH is 7.4 and optimum temperature is 60 °C. Substrates include urea and hydroxyurea.

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. [9]

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. [10] of repeating α-β subunits, each coupled pair of subunits has an active site, for a total of 12 active sites. [10] It plays an essential function for survival, neutralizing gastric acid by allowing urea to enter into periplasm via a proton-gated urea channel. [11] The presence of urease is used in the diagnosis of Helicobacter 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. [9]

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 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. [9]

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. [9] The three-chain organization is likely ancestral. [12]

Activity

The kcat/Km of urease in the processing of urea is 1014 times greater than the rate of the uncatalyzed elimination reaction of urea. [5] There are many reasons for this observation in nature. The proximity of urea to active groups in the active site along with the correct orientation of urea allow hydrolysis to occur rapidly. Urea alone is very stable due to the resonance forms it can adopt. The stability of urea is understood to be due to its resonance energy, which has been estimated at 30–40 kcal/mol. [5] This is because the zwitterionic resonance forms all donate electrons to the carbonyl carbon making it less of an electrophile making it less reactive to nucleophilic attack. [5]

Active site

The active site of ureases is located in the α (alpha) subunits. It is a bis-μ-hydroxo dimeric nickel center, with an interatomic distance of ~3.5 Å. [5] > The Ni(II) pair are weakly antiferromagnetically coupled. [13] X-ray absorption spectroscopy (XAS) studies of Canavalia ensiformis (jack bean), Klebsiella aerogenes and Sporosarcina pasteurii (formerly known as Bacillus pasteurii) [14] confirm 5–6 coordinate nickel ions with exclusively O/N ligation, including two imidazole ligands per nickel. [8] Urea substrate is proposed to displace aquo ligands.

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. [3] 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. [15] In Sporosarcina pasteurii urease, the flap was found in the open conformation, while its closed conformation is apparently needed for the reaction. [14]

When compared, the α subunits of Helicobacter pylori urease and other bacterial ureases align with the jack bean ureases. [15]

The binding of urea to the active site of urease has not been observed. [9]

Proposed mechanisms

Blakeley/Zerner

One mechanism for the catalysis of this reaction by urease was proposed by Blakely and Zerner. [16] It begins with a nucleophilic attack by the carbonyl oxygen of the urea 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 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 NH3 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. [17]

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. [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. In addition, the general acidic ligand required to protonate the urea nitrogen was not identified. [18] 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. [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. 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. [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. 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. [5]

Ciurli/Mangani

The mechanism proposed by Ciurli and Mangani [19] 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 ions in the active site. [14] One of which binds and activates urea, the other nickel ion binds and activates the nucleophilic water molecule. [14] 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 network, orienting the substrate into the catalytic cavity. [14] Urea binds to the five-coordinated nickel (Ni1) with the carbonyl oxygen atom. It approaches the six-coordinated nickel (Ni2) with one of its amino groups and subsequently bridges the two nickel centers. [14] 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. [14] 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. [14] 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. [14] 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. [14] The main structural difference between the Ciurli/Mangani mechanism and the other two is that it incorporates a nitrogen, oxygen bridging urea that is attacked by a bridging hydroxide. [17]

Action in pathogenesis

Bacterial ureases are often the mode of pathogenesis for many medical conditions. They are associated with hepatic encephalopathy / Hepatic coma, infection stones, and peptic ulceration. [20]

Infection stones

Infection induced urinary stones are a mixture of struvite (MgNH4PO4•6H2O) and carbonate apatite [Ca10(PO4)6•CO3]. [20] 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. [20] The resultant alkalinization results in stone crystallization. [20] In humans the microbial urease, Proteus mirabilis, is the most common in infection induced urinary stones. [21]

Urease in hepatic encephalopathy / hepatic coma

Studies have shown that Helicobacter pylori along with cirrhosis of the liver cause hepatic encephalopathy and hepatic coma. [22] Helicobacter pylori release microbial ureases into the stomach. The urease hydrolyzes urea to produce ammonia and carbonic acid. As the bacteria are localized to the stomach ammonia produced is readily taken up by the circulatory system from the gastric lumen. [22] This results in elevated ammonia levels in the blood, a condition known as hyperammonemia; eradication of Helicobacter pylori show marked decreases in ammonia levels. [22]

Urease in peptic ulcers

Helicobacter pylori is also the cause of peptic ulcers with its manifestation in 55–68% reported cases. [23] This was confirmed by decreased ulcer bleeding and ulcer reoccurrence after eradication of the pathogen. [23] In the stomach there is an increase in pH of the mucosal lining as a result of urea hydrolysis, which prevents movement of hydrogen ions between gastric glands and gastric lumen. [20] 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. [20] [24]

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. [25] 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. [26] 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. [27]

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. [28] Phenyl phosphorodiamidate and N-(n-butyl)thiophosphoric triamide are two such inhibitors. [29]

Biomineralization

By promoting the formation of calcium carbonate, ureases are potentially useful for biomineralization-inspired processes. [30] Notably, microbiologically induced formation of calcium carbonate can be used in making bioconcrete. [31]

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. [12]

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 biopesticides. [12]

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:

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 produce urease as a survival mechanism. Known structural classes of inhibitors include: [33] [34]

Extraction

First isolated as a crystal in 1926 by Sumner, using acetone solvation and centrifuging. [36] Modern biochemistry has increased its demand for urease. Jack bean meal, [37] watermelon seeds, [38] and pea seeds [39] have all proven useful sources of urease.

See also

Related Research Articles

Urea, also called carbamide, is an organic compound with chemical formula CO(NH2)2. This amide has two amino groups joined by a carbonyl functional group. It is thus the simplest amide of carbamic acid.

<span class="mw-page-title-main">Urea breath test</span> Medical test for a bacteria infection

The urea breath test is a rapid diagnostic procedure used to identify infections by Helicobacter pylori, a spiral bacterium implicated in gastritis, gastric ulcer, and peptic ulcer disease. It is based upon the ability of H. pylori to convert urea to ammonia and carbon dioxide. Urea breath tests are recommended in leading society guidelines as a preferred non-invasive choice for detecting H. pylori before and after treatment.

<i>Helicobacter pylori</i> Species of bacteria

Helicobacter pylori, previously known as Campylobacter pylori, is a gram-negative, flagellated, helical bacterium. Mutants can have a rod or curved rod shape, and these are less effective. Its helical body is thought to have evolved in order to penetrate the mucous lining of the stomach, helped by its flagella, and thereby establish infection. The bacterium was first identified as the causal agent of gastric ulcers in 1983 by the Australian doctors Barry Marshall and Robin Warren.

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<span class="mw-page-title-main">Rapid urease test</span> Test for Heliobacter pylori infection

Rapid urease test, also known as the CLO test, is a rapid diagnostic test for diagnosis of Helicobacter pylori. The basis of the test is the ability of H. pylori to secrete the urease enzyme, which catalyzes the conversion of urea to ammonia and carbon dioxide.

<span class="mw-page-title-main">Argininosuccinate synthase</span> Enzyme

Argininosuccinate synthase or synthetase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the ASS gene located on chromosome 9.

Carbamoyl phosphate synthetase I (CPS I) is a ligase enzyme located in the mitochondria involved in the production of urea. Carbamoyl phosphate synthetase I (CPS1 or CPSI) transfers an ammonia molecule to a molecule of bicarbonate that has been phosphorylated by a molecule of ATP. The resulting carbamate is then phosphorylated with another molecule of ATP. The resulting molecule of carbamoyl phosphate leaves the enzyme.

<span class="mw-page-title-main">Pyruvate dehydrogenase</span> Class of enzymes

Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate.

<span class="mw-page-title-main">Carboxypeptidase A</span>

Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes peptide bonds of C-terminal residues with aromatic or aliphatic side-chains. Most scientists in the field now refer to this enzyme as CPA1, and to a related pancreatic carboxypeptidase as CPA2.

<span class="mw-page-title-main">Carbamoyl phosphate synthetase</span> Class of enzymes

Carbamoyl phosphate synthetase catalyzes the ATP-dependent synthesis of carbamoyl phosphate from glutamine or ammonia and bicarbonate. This enzyme catalyzes the reaction of ATP and bicarbonate to produce carboxy phosphate and ADP. Carboxy phosphate reacts with ammonia to give carbamic acid. In turn, carbamic acid reacts with a second ATP to give carbamoyl phosphate plus ADP.

In enzymology, a nickel-transporting ATPase (EC 3.6.3.24) is an enzyme that catalyzes the chemical reaction

In enzymology, an aminoacylase (EC 3.5.1.14) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Dioxygenase</span> Class of enzymes

Dioxygenases are oxidoreductase enzymes. Aerobic life, from simple single-celled bacteria species to complex eukaryotic organisms, has evolved to depend on the oxidizing power of dioxygen in various metabolic pathways. From energetic adenosine triphosphate (ATP) generation to xenobiotic degradation, the use of dioxygen as a biological oxidant is widespread and varied in the exact mechanism of its use. Enzymes employ many different schemes to use dioxygen, and this largely depends on the substrate and reaction at hand.

[NiFe] hydrogenase is a type of hydrogenase, which is an oxidative enzyme that reversibly converts molecular hydrogen in prokaryotes including Bacteria and Archaea. The catalytic site on the enzyme provides simple hydrogen-metabolizing microorganisms a redox mechanism by which to store and utilize energy via the reaction

Lysine carboxypeptidase is an enzyme. This enzyme catalyses the following chemical reaction:

<span class="mw-page-title-main">Nickel superoxide dismutase</span>

Nickel superoxide dismutase (Ni-SOD) is a metalloenzyme that, like the other superoxide dismutases, protects cells from oxidative damage by catalyzing the disproportionation of the cytotoxic superoxide radical to hydrogen peroxide and molecular oxygen. Superoxide is a reactive oxygen species that is produced in large amounts during photosynthesis and aerobic cellular respiration. The equation for the disproportionation of superoxide is shown below:

<span class="mw-page-title-main">CO-methylating acetyl-CoA synthase</span> Enzyme

Acetyl-CoA synthase (ACS), not to be confused with acetyl-CoA synthetase or acetate-CoA ligase, is a nickel-containing enzyme involved in the metabolic processes of cells. Together with carbon monoxide dehydrogenase (CODH), it forms the bifunctional enzyme Acetyl-CoA Synthase/Carbon Monoxide Dehydrogenase (ACS/CODH) found in anaerobic microorganisms such as archaea and bacteria. The ACS/CODH enzyme works primarily through the Wood–Ljungdahl pathway which converts carbon dioxide to Acetyl-CoA. The recommended name for this enzyme is CO-methylating acetyl-CoA synthase.

<span class="mw-page-title-main">Resistance-nodulation-cell division superfamily</span>

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Nickel compounds are chemical compounds containing the element nickel which is a member of the group 10 of the periodic table. Most compounds in the group have an oxidation state of +2. Nickel is classified as a transition metal with nickel(II) having much chemical behaviour in common with iron(II) and cobalt(II). Many salts of nickel(II) are isomorphous with salts of magnesium due to the ionic radii of the cations being almost the same. Nickel forms many coordination complexes. Nickel tetracarbonyl was the first pure metal carbonyl produced, and is unusual in its volatility. Metalloproteins containing nickel are found in biological systems.

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References

  1. ↑ PDB: 2KAU ​; Jabri E, Carr MB, Hausinger RP, Karplus PA (May 1995). "The crystal structure of urease from Klebsiella aerogenes". Science. 268 (5213): 998–1004. Bibcode:1995Sci...268..998J. doi:10.1126/science.7754395. PMID   7754395.
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  18. ↑ Jabri E, Carr MB, Hausinger RP, Karplus PA (May 19, 1995). "The crystal structure of urease from Klebsiella aerogenes". Science. 268 (5213): 998–1004. Bibcode:1995Sci...268..998J. doi:10.1126/science.7754395. PMID   7754395.
  19. ↑ Zambelli B, Musiani F, Benini S, Ciurli S (19 July 2011). "Chemistry of Ni2+ in Urease: Sensing, Trafficking, and Catalysis". Accounts of Chemical Research. 44 (7): 520–530. doi:10.1021/ar200041k. PMID   21542631.
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