Why is urea not converted to ammonia in the body?

Question

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?

Answer 1

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.

Answer 2

[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.