User:Katgirl259/Urea Toxicity

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Reactions[edit]

Urea Decomposition in Water[edit]

Urea decomposition in water

Hydrolysis, which is the process of a chemical decomposition in the conjunction of water, is the first of the two equilibrium reactions that occur in aqueous urea. The reaction forms one equivalent of ammonia and one equivalent of carbamic acid; carbamic acid formation is endothermic; ammonia formation is exothermic.[1] The overall reaction is endothermic therefore requiring heat to take place. The carbamic acid quickly decomposes to form gaseous carbon dioxide and another equivalent of ammonia. The reaction is endothermic because the solvating molecules requires energy and because urea is commercially available solid energy is required to dissolve it.[2]

Urea Decomposition via Urease[edit]

Urease catalyzed decomposition

Urea is also able to react with water in the presence of the catalyst, urease. The reaction is 1014 times faster than the uncatalyzed rate; however, some of the urea is volatilized at the surface and lost as ammonia gas to the atmosphere.[3] [4]

Urease is an aminohydrolase, which is an enzyme that acts specifically on amino groups of substrates.[5] Urease catalyzes the hydrolysis of urea using dimeric nickel to form ammonium.[6] Specifically, urease catalyzes the hydrolysis of urea to produce ammonia and carbamate; the carbamate produced is then degraded by hydrolysis to produce another ammonia and carbon dioxide.[7]

Although the mechanism is debated, the most widely accepted mechanism is that the first nickel binds and activates nucleophilic hydroxide ion (or water) while the second nickel binds and activates the substrate (urea).[8] Also, cysteine is important in positioning the substrate through hydrogen bond interactions, between the sulfur that is a part of the cysteine and the hydrogen on the nitrogen of the urea.[9] Alanine residues are also important mechanistically because they increase basicity, which makes it more willing to accept electrons and thus react faster: this allows it to bond more strongly to the second nickel. This process increases the reactivity by stabilizing the intermediate.[8] 

Thermal Urea Decomposition[edit]

Heat catalyzed decomposition of urea

The decomposition of urea is an endothermic reaction, as heat is required to break chemical bonds in the compounds undergoing decomposition, which is essentially thermal decomposition. The thermal decomposition of urea is very complex.[10] The effects of different heating rates influence the decomposition. As temperature increases, the reaction becomes more exothermic. The reaction is more efficient at higher temperatures, but is capable of reacting at room temperature. The reaction is least efficient when the urea is heated at low pressures.[11]

In a decomposition reaction, urea is decomposed into isocyanic acid, which is then hydrolyzed into carbon dioxide and ammonia.[12] The production of ammonia and isocyanic acid occurs at the same time, but when isocyanic acid starts diminishing, the production of ammonia increases. The presence of carbon dioxide is only seen at the end of the reaction.

Ethyl Carbamate Synthesis[edit]

Urethane formation from ethanol and urea
Urethane Formation Mechanism

The reaction between urea and ethanol synthesizes ethyl carbamate, which is also known as urethane, and the ammonia byproduct.[13] The thermodynamics of the reaction allow it to proceed without a catalyst but it can occur at faster rates in the presence of a catalyst.[14] The reaction occurs at room temperature, but as the temperature increases, so does the rate. The main factors that affect product formation are temperature and time.[15] The reaction proceeds by the lone pair electrons on the oxygen of the ethanol attacking the carbonyl carbon. This forces the carbonyl electrons from the double bond to the oxygen, resulting in a negative charge on that oxygen and creates a positive charge on the oxygen that attacked in the first place. This forms a charged tetrahedral intermediate, which collapses and favors kicking off the better leaving group, which is an amidogen (NH2). After kicking off the NH2 group, the carbonyl is able to reform due to the electron rich oxygen. The NH2 group that was just kicked off is highly reactive because of the negative charge on the nitrogen; the negatively charged nitrogen deprotonates the oxygen that has the positive charge, resulting in the formation of ethyl carbamate and the ammonia byproduct.[16]

Barbituric Acid Synthesis[edit]

Barbituric acid formation from ethyl malonate and urea
Intramolecular Barbituric Acid Formation

In order to synthesize barbituric acid, a reaction between diethyl malonate and urea must take place in the presence of sodium ethoxide (ethanol and sodium); sodium ethoxide acts strong base that is used in this reaction.[17] The barbituric acid forms from the lone pair electrons attached on one of the nitrogens on urea, reacting with the esters of the substituted malonic acid, which is a dicarboxylic acid.[18] This attack on the dicarboxylic acid creates a charged tetrahedral intermediate. The charged tetrahedral collapses, pushing the electrons from the carbonyl oxygen back into a double bond forcing the ethanol substituent to come off. An intramolecular reaction with the unreacted nitrogen from the urea and the unreacted carbonyl carbon finally forms the cyclic compound, barbituric aid, and two ethanol compounds.[19] The mechanism for the second attacks occurs by the same principles as the first.

This reaction is the condensation of urea and malonic acid. Under ideal conditions, 70°C, the reaction goes to completion; however, the reaction occurs to some degree in the environment.[17]




Interactions with Compounds[edit]

Ammonia[edit]

Ammonia exists in equilibrium.[20] The difference between ammonia and ammonium is important because the two compounds have different toxicities.[21] Whereas ammonium itself is the more toxic derivative, ammonia is considered the more toxic compound because it is more bioavailable. The bioavailability has to do with the ability of compounds to be taken up in an organism. The bioavailability in fish has to do with the ability of charged ions (ammonium) to diffuse across the gills into the fish being lower than the ability of uncharged compounds (ammonia) to diffuse across the gills into the fish.[22] Because the two species exist in equilibrium with each other in the environment, the concentrations of ammonia and ammonium, and thus the overall toxicity, can be affected by Le Chatelier's principle.[23] Ammonia toxicity increases with the increase in pH, 1 unit resulting in 10 times greater toxicity, and with temperature, 10° C increase results in a 2 times greater toxicity. The toxicity of ammonia is dependent on the organism; however, in general 0.2-2.0 mg/L is considered toxic.[24]

Ammonia toxicity and equilibrium

Ammonia toxicity can result in fish lung activity becoming impaired. This happens through hyperplasia of the gills, which is an increase in the number of cells around the gills. This increase in cell number results in an inhibition of gas exchange.[25] The impaired gill function is also brought upon by burning of the gills and lungs. The gills are burned through both chemical and thermal burns. The chemical burns are a result of ammonia reacting with water inside the fish creating hydroxide ions (OH-), which has caustic properties on tissues. This caustic action is a result of the saponification reaction of OH- cleaving the esters bonds present in membrane lipids in tissue. This reaction causes the lipids to dissolve away, decreasing membrane integrity.[26] The reaction is exothermic and because of this, when ammonia reacts with water, it produces hydroxide ion, ammonium ion, and heat. This heat is lost to the environment and the environment in this case is the sensitive lung tissue of the fish.[23][25]

Ammonium's effect on Na+ and K+ channels

Ammonium can build up in the organs of the organism because it is not easily diffused. Ammonium interacts with Na+/K+ channels in the cells of the body. These channels are important for moving potassium ions (K+) into the cell and sodium ions (Na+) out of the cell.[27] This movement of ions is how nerve impulses are transmitted in vertebrates. Ammonium ions (NH4+) build up in organs and they compete with K+ ions on the extracellular side of the channel.  In order for protein functions to be fulfilled by particular ions, charge and size criteria must be met. The K+ and NH4+ ions have similar charges so the ammonium is able to bind to the active site just as K+, but because the ammonium is smaller than the potassium, the channel protein does not interact with the NH4+ in the same manner that K+ would. This means that the channel itself does not undergo a conformational change, which would have allowed the ions to be exchanged. In this way, the ammonium acts as a competitive inhibitor with the potassium. Because there is no exchange of ions, there is no depolarization and repolarization, thus no action potential. This results in nerve signals being trapped in ammonium inhibited channels. The inability of signal propagation leads to a depressed or inhibited central nervous system (CNS), which can lead to a variety of biological effects from strokes to neurological disorders.[28][29]

Barbituric Acid[edit]

Barbituric acid binds to positive allosteric modulation sites, increasing the effectiveness of the receptor, thus depressing the central nervous system.

Barbituric acid derivatives barbiturates are commonly used as CNS depressants resulting in sedation.[30] Barbuturic acid has been shown to affect the GABA neuroreceptor, which is a neurotransmitter that is normally inhibited by Gamma-Aminobutyric acid (GABA). The GABA receptor exist as two classes, the GABAA, or ionotropic, and GABAB, or G-protein coupled receptors. The ionotropic receptors are receptors that allow ions to pass with a bound ligand and are class of GABA receptors directly affected by barbituric acid. GABA works to inhibit the receptor to minimize the flow of chlorine ions (Cl-) into the cell. This keeps the action potential around the normal -70 mV.[31] Barbituric acid inhibits the activity of the GABA, thus increasing the effectiveness of the receptor. Barbituric acid’s mechanism of action is through the positive allosteric modulation (PAM) sites. The Met 236 and Met 286 residues on the β-subunits of the GABA receptor interact directly with the barbituric acid through hydrogen bonding. This binding causes an allosteric modulation which result in the Cl-­ channel being opened for a longer duration of time.[32] This results in more Cl- ions flowing into the cell, which lowers the action potential beyond -70 mV. Because of the more negative action potential, the nervous system must input more energy to depolarize nerve cells in order to culminate in a neurological response. As a result of a higher energy requirement, the CNS is unable to efficiently or effectively transmit propagate signals.[33][34] This results in a suppressed CNS and can lead to a variety of implications such as disease and most severely death.[35]

Urethane[edit]

Urethane interactions with glutamate receptors

Urethane is used in the laboratory setting as a general anesthetic, usually for mice.[36] Urethane works through a similar mechanism as the aforementioned barbituric acid; however, urethane targets a wide class of glutamate neuroreceptors: N-Methyl-D-aspartic acid (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainite.[37] Although the exact mechanism is unknown, urethane produces a sigmoidal curve, which translates to allosteric regulation. It is likely that the interactions at the allosteric site occurs through hydrogen bond interactions between glutamate residues (which are prevalent in glutamate receptors) and the amide functional group of urethane.[33][38] Because of its effect as a general anesthetic, it also inhibits the CNS and can result in neurological disorders as well as nervous system deterioration.[33][38]

References[edit]

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External links[edit]

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