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Why is urea not converted to ammonia in the body?

Why is urea not converted to ammonia in the body?



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After the liver processes metabolites to produce urea and other by-products, these travel in the blood to the heart, then they are oxygenated, and some travel through the renal artery to the kidneys.

Urea in water can decompose into ammonia which is toxic, as mentioned in a textbook page no 170 (6), under production of ammonia.

Reactant and product are at equilibrium. Also a gaseous product, CO2, is present which could potentially escape during oxygenation of blood. Hence, according to Le Chatelier's principle, an equilibrium shift towards the product is possible

NH2CONH2 + 2H2O → (NH4)2CO3 ⇌ 2NH3 + H2O + CO2

The chance of urea decomposing into ammonia is high while travelling in the blood (i.e taking long route) and in the bladder, but it still does not happen. Why not?


The answer to this question is quite simply this:

The activation energy for the uncatalysed reaction is such that the amount of decomposition of urea in aqueous solution at blood temperature and pH is negligible in the time taken for the transfer of urea to the kidney.

The literature supporting this is very old, so I shall first cite a relatively recent (2004) and (I think) freely available paper by Robert P. Hausinger on urease in which he writes:

The substrate [i.e. urea] is highly resonance stabilized (30 to 40 kcal/mol), thus decreasing the reactivity of its carbonyl carbon so that spontaneous hydrolysis of urea has never been observed. Rather, urea decomposes in solution (with an estimated half-life of 3.6 years at 38°C) by the slow elimination of ammonia to form cyanic acid (17)

Reference [17] is a paper by Zerner in Bio-organic Chemistry from 1991 which requires a library subscription. In effect it quotes the same half-life:

The urea molecule is very stable. Between pH 2 and pH 12, the nonenzymatic decomposition of urea in aqueous media is independent of pH and has a half-life of 3.6 years at 38°C (36-38).

References 36 is a book written in 1923, and references 37 and 38 date from 1942 and 1955, respectively. I have not checked the latter, but can if anyone demands it.

All of which is not surprising, as the purpose of the urea cycle in mammals (etc.) is to eliminate toxic ammonia, and, as @Fizz points out, the enzyme urease is needed by bacteria that utilize the compound.


[Partial answer]

[OP claim:] Urea in water can decompose into ammonia which is toxic.

Probably not as easily as you think. If Wikipedia is correct:

Urea alone is very stable due to the resonance forms it can adopt.

Some bacteria use urease to catalyze the reaction by 14 orders of magnitude (says Wikipedia).

There are some primary sources from the 1930s on the resonance forms of urea; I've not read them just yet.

From experimental data in solutions (not blood), urea would be close to its maximum stability in blood, pH-wise at least:

The stability analysis shows that urea is more stable at the pH range of 4-8 and the stability of urea decreases by increase in temperature for all pH values. Within the experimental range of temperature and initial urea concentration values, the lowest urea degradation was found with lactate buffer pH 6.0. The urea decomposition rate in solution and pharmaceutical preparations shows the dependence of the initial urea concentrations. At higher initial urea concentrations, the rate of degradation is a decreasing function with time. This suggests that the reverse reaction is a factor in the degradation of concentrated urea solution.

As for the reaction speed in terms that even I can understand:

The urea molecule is very stable. Between pH 2 and pH 12, the nonenzymatic decomposition of urea in aqueous media is independent of pH and has a half-life of 3.6 years at 38°C.

(This review cites data from older papers, so presumably they had less sensitive methods, so they concluded a wider pH range where it's most stable.)

For the chemistry experts, there exists a lot more information on the kinetics of the reaction.


Why is urea not converted to ammonia in the body? - Biology

Of the four major macromolecules in biological systems, both proteins and nucleic acids contain nitrogen. During the catabolism, or breakdown, of nitrogen-containing macromolecules, carbon, hydrogen, and oxygen are extracted and stored in the form of carbohydrates and fats. Excess nitrogen is excreted from the body. Nitrogenous wastes tend to form toxic ammonia, which raises the pH of body fluids. The formation of ammonia itself requires energy in the form of ATP and large quantities of water to dilute it out of a biological system. Animals that live in aquatic environments tend to release ammonia into the water. Animals that excrete ammonia are said to be ammonotelic. Terrestrial organisms have evolved other mechanisms to excrete nitrogenous wastes. The animals must detoxify ammonia by converting it into a relatively nontoxic form such as urea or uric acid. Mammals, including humans, produce urea, whereas reptiles and many terrestrial invertebrates produce uric acid. Animals that secrete urea as the primary nitrogenous waste material are called ureotelic animals.


Limiting protein in the diet can help treat these disorders by reducing the amount of nitrogen waste the body produces. (The waste is in the form of ammonia.) Special low-protein infant and toddler formulas are available.

It is important that a provider guides protein intake. The provider can balance the amount of protein the baby gets so that it is enough for growth, but not enough to cause symptoms.

It is very important for people with these disorders to avoid fasting.

People with urea cycle abnormalities must also be very careful under times of physical stress, such as when they have infections. Stress, such as a fever, can cause the body to break down its own proteins. These extra proteins can make it hard for the abnormal urea cycle to remove the byproducts.

Develop a plan with your provider for when you are sick to avoid all protein, drink high carbohydrate drinks, and get enough fluids.

Most people with urea cycle disorders will need to stay in the hospital at some point. During such times, they may be treated with medicines that help the body remove nitrogen-containing wastes. Dialysis may help rid the body of excess ammonia during extreme illness. Some people may need a liver transplant.


There are several inherited diseases of the urea cycle caused by mutations in genes encoding one or another of the necessary enzymes. The most common of these is an inherited deficiency of ornithine transcarbamylase, an enzyme needed for the conversion of ornithine to citrulline. It results in elevated levels of ammonia that may be so high as to be life-threatening. It is an X-linked disorder therefore most commonly seen in males. It can be cured by a liver transplant. It can also be caused by a liver transplant! In 1998, an Austrian woman was given a new liver from a male cadaver who - unknown to the surgeons - had a mutation in his single ornithine transcarbamylase gene. The woman's blood level of ammonia shot up, and she died a few days later.

Humans also excrete a second nitrogenous waste, uric acid. It is the product of nucleic acid, not protein, metabolism. It is produced within peroxisomes. Uric acid is only slightly soluble in water and easily precipitates out of solution forming needlelike crystals of sodium urate. These contribute to the formation of kidney stones and produce the excruciating pain of gout when deposited in the joints.

Curiously, our kidneys reclaim most of the uric acid filtered at the glomeruli. Why, if it can cause problems?

  • Uric acid is a potent antioxidant and thus can protect cells from damage by reactive oxygen species (ROS).
  • The concentration of uric acid is 100-times greater in the cytosol than in the extracellular fluid. So when lethally-damaged cells release their contents, crystals of uric acid form in the vicinity. These enhance the ability of nearby dendritic cells to "present" any antigens released at the same time to T cells leading to a stronger immune response.

So the risk of kidney stones and gout may be the price we pay for these protections.

Most mammals have an enzyme - uricas - for breaking uric acid down into a soluble product. However, during the evolution of great apes and humans, the gene encoding uricase became inactive. A predisposition to gout is our legacy.

Uric acid is the chief nitrogenous waste of insects, lizards and snakes and birds. It is the whitish material that birds leave on statues. These animals convert the waste products of protein metabolism as well as nucleic acid metabolism into uric acid. Because of its low solubility in water, these animals are able to eliminate waste nitrogen with little loss of water.


Why is urea toxic?

It contains ammonia which can harm human cells over time especially brain cells because it is very corrosive.

Hope that helps

(Original post by may_1)
It contains ammonia which can harm human cells over time especially brain cells because it is very corrosive.

Hope that helps

(Original post by morgan8002)
I'm not sure. It's quite basic, but the blood is buffered against PH change.


It doesn't contain ammonia.

It does. The amino acids are converted from protein into metabolic waste. This means alpha-amino nitrogen is removed, which results in ammonia being formed. Of course, it's not at its strongest, and is only harmful at high concentrations - which typically does not occur due to it being stored and dispelled from the bladder! It's more toxic due to its solubility than anything else.

(Original post by flippantri)
It does. The amino acids are converted from protein into metabolic waste. This means alpha-amino nitrogen is removed, which results in ammonia being formed.

Of course, it's not at its strongest, and is only harmful at high concentrations - which typically does not occur due to it being stored and dispelled from the bladder!
It's more toxic due to its solubility than anything else.

Aw, no need to be bitter. I was explaining how ammonia is found in urea which leads to its toxicity, which answers OP's question - so it kind of is relevant.

(Original post by flippantri)
Aw, no need to be bitter. I was explaining how ammonia is found in urea which leads to its toxicity, which answers OP's question - so it kind of is relevant. (Original post by flippantri)
Aw, no need to be bitter. I was explaining how ammonia is found in urea which leads to its toxicity, which answers OP's question - so it kind of is relevant.

Urea is a metabolic product of ammonia, that doesn't mean it contains ammonia? Glucose is broken down to acetyl CoA in some of the steps of respiration, that doesn't mean acetyl CoA contains glucose? If you want an even simpler example, when you breathe out CO2 and H2O as products of respiration, are you breathing out glucose too?

Bubblybabybling to answer your question, urea in high concentrations in the blood is called uraemia which can cause cell death, oxidative stress, and interferes with some cell signalling, other cell chemical reactions as well as proliferation. It has a chaotropic effect on the cell membrane (interferes with hydrogen-bonding networks) which causes many of the issues I've just mentioned. It can also cause water retention and its associated conditions (high blood pressure, heart disease, oedema, nausea/loss of appetite leading to malnutrition/anaemia etc). It also directly damages nerves.

Hope this helped

(Original post by yasaminO_o)
Urea is a metabolic product of ammonia, that doesn't mean it contains ammonia? Glucose is broken down to acetyl CoA in some of the steps of respiration, that doesn't mean acetyl CoA contains glucose? If you want an even simpler example, when you breathe out CO2 and H2O as products of respiration, are you breathing out glucose too?

Bubblybabybling to answer your question, urea in high concentrations in the blood is called uraemia which can cause cell death, oxidative stress, and interferes with some cell signalling, other cell chemical reactions as well as proliferation. It has a chaotropic effect on the cell membrane (interferes with hydrogen-bonding networks) which causes many of the issues I've just mentioned. It can also cause water retention and its associated conditions (high blood pressure, heart disease, oedema, nausea/loss of appetite leading to malnutrition/anaemia etc). It also directly damages nerves.

Hope this helped

Okay, alright, I see how my wording was wrong and confusing. Thanks for the corrections!

Contents

For plants to absorb nitrogen from urea it must first be broken down:

Urease is a naturally occurring enzyme that catalyzes the hydrolysis of urea to unstable carbamic acid. Rapid decomposition of carbamic acid occurs without enzyme catalysis to form ammonia and carbon dioxide. [2] [3] The ammonia will likely escape to the atmosphere unless it reacts with water to form ammonium (NH4 + ) according to the following reaction:


This is important because ammonium is a plant available source of nitrogen while ammonia is not. [4] Additionally, the formation of the hydroxide ion may cause soils around the applied urea particle to have a pH around 9.0 which increases ammonia volatilization. This area is also highly toxic due to elevated ammonia concentration for several hours so it is recommended that urea based fertilizers not be applied or banded with planted seed at a rate that exceeds 10–20 kg/ha, depending on the crop species. [5] It is important that there is adequate moisture because up to thirty percent of the available nitrogen can be lost through atmospheric volatilization within seventy-two hours of application. [6]

Ammonia volatilization reduces the economic efficiency of agricultural cropping systems. Either yield will be reduced or additional costs will be incurred from additional nitrogen fertilizer. The amount of ammonia volatilization depends on several environmental factors, including temperature, pH, and the soil water content. Additionally, the amount of surface residue and time between urea application and precipitation are also critical. Generally speaking, volatilization will be lower when urea is applied during the wetter and cooler conditions that generally occur in early spring (March and April). However, drying surface soil and rising temperatures as spring progresses increases the probability of ammonia volatilization. [1] Ideally, a manager should attempt to apply nitrogen immediately before a moderate rain event (0.1 inch), allowing urea to dissolve and move into the soil. However, this is not always possible. The soil's pH also has a strong effect on the amount of volatilization. Specifically, highly alkaline soils (pH

8.2 or higher) have proven to increase urea hydrolysis. One study has shown complete hydrolysis of urea within two days of application on such soils. In acidic soils (pH 5.2) the urea took twice as long to hydrolyze. [7] Surface residues, such as thatch and plant stubble exhibit increased urease activity. Soils that have high organic matter content also tend to have higher urease concentrations. More urease results in greater hydrolysis of urea and ammonia volatilization, particularly if urea fails to move into the soil. [8]

Fertilizer is often applied when field conditions are not optimal, particularly in large scale operations. Most studies, [1] [9] indicate that nitrogen losses can be reduced in these situations when a urease inhibitor is applied to the fertilizer. Urease inhibitors prevent the urease enzyme from breaking down the urea. This increases the probability that urea will be absorbed into the soil after a rain event rather than volatilized into the atmosphere. This causes subsequent hydrolyzation to occur below the soil surface and decreases atmospheric losses. The use of inhibitors also decreases the localized zones of high pH common with untreated urea. [10]


There are several inherited diseases of the urea cycle caused by mutations in genes encoding one or another of the necessary enzymes. The most common of these is an inherited deficiency of ornithine transcarbamylase, an enzyme needed for the conversion of ornithine to citrulline. It results in elevated levels of ammonia that may be so high as to be life-threatening. It is an X-linked disorder therefore most commonly seen in males. It can be cured by a liver transplant. It can also be caused by a liver transplant! In 1998, an Austrian woman was given a new liver from a male cadaver who - unknown to the surgeons - had a mutation in his single ornithine transcarbamylase gene. The woman's blood level of ammonia shot up, and she died a few days later.

Humans also excrete a second nitrogenous waste, uric acid. It is the product of nucleic acid, not protein, metabolism. It is produced within peroxisomes. Uric acid is only slightly soluble in water and easily precipitates out of solution forming needlelike crystals of sodium urate. These contribute to the formation of kidney stones and produce the excruciating pain of gout when deposited in the joints.

Curiously, our kidneys reclaim most of the uric acid filtered at the glomeruli. Why, if it can cause problems?

  • Uric acid is a potent antioxidant and thus can protect cells from damage by reactive oxygen species (ROS).
  • The concentration of uric acid is 100-times greater in the cytosol than in the extracellular fluid. So when lethally-damaged cells release their contents, crystals of uric acid form in the vicinity. These enhance the ability of nearby dendritic cells to "present" any antigens released at the same time to T cells leading to a stronger immune response.

So the risk of kidney stones and gout may be the price we pay for these protections.

Most mammals have an enzyme - uricas - for breaking uric acid down into a soluble product. However, during the evolution of great apes and humans, the gene encoding uricase became inactive. A predisposition to gout is our legacy.

Uric acid is the chief nitrogenous waste of insects, lizards and snakes and birds. It is the whitish material that birds leave on statues. These animals convert the waste products of protein metabolism as well as nucleic acid metabolism into uric acid. Because of its low solubility in water, these animals are able to eliminate waste nitrogen with little loss of water.


What happens during an ammonia levels test?

A health care professional will take a blood sample from a vein in your arm, using a small needle. After the needle is inserted, a small amount of blood will be collected into a test tube or vial. You may feel a little sting when the needle goes in or out. This usually takes less than five minutes.

To test a newborn, a health care provider will clean your baby's heel with alcohol and poke the heel with a small needle. The provider will collect a few drops of blood and put a bandage on the site.


Nitrogenous Waste in Terrestrial Animals: The Urea Cycle

The urea cycle is the primary mechanism by which mammals convert ammonia to urea. Urea is made in the liver and excreted in urine. The overall chemical reaction by which ammonia is converted to urea is 2 NH3 (ammonia) + CO2 + 3 ATP + H2O → H2N-CO-NH2 (urea) + 2 ADP + 4 Pi + AMP.

The urea cycle utilizes five intermediate steps, catalyzed by five different enzymes, to convert ammonia to urea, as shown in [link]. The amino acid L-ornithine gets converted into different intermediates before being regenerated at the end of the urea cycle. Hence, the urea cycle is also referred to as the ornithine cycle. The enzyme ornithine transcarbamylase catalyzes a key step in the urea cycle and its deficiency can lead to accumulation of toxic levels of ammonia in the body. The first two reactions occur in the mitochondria and the last three reactions occur in the cytosol. Urea concentration in the blood, called blood urea nitrogen or BUN, is used as an indicator of kidney function.



In terms of evolution, why might the urea cycle have evolved in organisms?

It is believed that the urea cycle evolved to adapt to a changing environment when terrestrial life forms evolved. Arid conditions probably led to the evolution of the uric acid pathway as a means of conserving water.

Compare and contrast the formation of urea and uric acid.

The urea cycle is the primary mechanism by which mammals convert ammonia to urea. Urea is made in the liver and excreted in urine. The urea cycle utilizes five intermediate steps, catalyzed by five different enzymes, to convert ammonia to urea. Birds, reptiles, and insects, on the other hand, convert toxic ammonia to uric acid instead of urea. Conversion of ammonia to uric acid requires more energy and is much more complex than conversion of ammonia to urea.