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Term Paper # 1. Introduction to Urea Formation:

The deamination of amino acids forms large amounts of ammonia which, if allowed to accumulate, would be highly toxic. Normally, the blood contains only 0.1 to 0.2 mg percent of ammonia nitrogen, an amount so small that special techniques are required for its determination. A concentration of 5 mg percent is fatal to the rabbit. In view of the toxicity of ammonia, it is not surprising that the animal body detoxifies it rapidly in the liver before release into the systemic circulation.

In man and other mammals detoxication is achieved largely by conversion to urea, whereas in reptiles and birds uric acid is formed. Considerable ammonia nitrogen may be excreted in the urine, but this is formed in the kidney for excretion in the urine and does not appreciably increase the ammonia content of the systemic blood.

Term Paper # 2. Site of Urea Formation:

Conclusive evidence that the liver is the site of urea formation was afforded by the work of Bollman, Mann and Magath on dogs from which the liver or kidneys or both had been removed. If the kidneys alone were removed, preventing excretion, the blood urea fell. If both the kidneys and liver were removed, the blood urea remained constant, since urea was neither being formed nor excreted.


In vitro work has shown that the enzymes concerned in the conversion of ammonia to urea are localized in the liver.

Term Paper # 3. Chemical Mechanisms of Urea Formation:  

Krebs-Henseleit Cycle:

Krebs and Henseleit working with liver slices established the general chemical mechanisms by which ammonia is converted to urea. These workers incubated liver slices with ammonium salts, bicarbonate as a source of carbon dioxide, and lactate as a source
of energy, and studied the rate of urea formation. They found that the addition of ornithine greatly increased the rate of urea production. Citrulline had a similar effect.

The amino acid, arginine, was found to be an intermediate product of the reaction. The liver contains the enzyme, arginase, which hydrolyzes arginine to ornithine and urea. Balance experiments showed that during urea synthesis the sum of the concentrations, ornithine + arginine, did not decrease appreciably, while the quantity of ammonia disappearing was approximately equivalent to the urea formed.


The ornithine was not used up, showing its action to be catalytic. Although citrulline was involved in the synthesis, it did not act catalytically, since one of its nitrogen atoms appeared in the urea formed.

The Krebs and Henseleit proposed a cyclic mechanism for urea synthesis involving ornithine, citrulline, arginine, ammonia, and carbon dioxide as follows:

Krebs--Henseleit Cycle

Two molecules of NH3 and one molecule of CO2 are converted to a molecule of urea for each turn of the cycle, and the ornithine is regenerated. The synthesis of urea involves the primary “fixation” of both CO2 and NH3.


Although the overall process of urea synthesis as outlined in the Krebs-Henseleit cycle has been shown to be correct, it has been found that formation of citrulline, and the conversion of citrulline to arginine, are complex processes.

i. Formation of Carbamyl Phosphate:

The first stage in the synthesis of urea in animals may be considered to be the formation of carbamyl phosphate the reaction being catalyzed by carbamyl phosphate synthetase. Carbamyl phosphate supplies one of the nitrogen atoms for urea synthesis.

The enzyme carbamyl phosphate synthetase catalyzes a two-step reaction leading to the formation of this high-energy compound. It has been known for some time that acetyl-glutamate and Mg++ are required normally in the synthesis.


The two reactions, requiring 2 ATP, are as follows:

Cohen and others have studied the function of acetylglutamate using purified enzyme preparations and concluded that the activator may stabilize the active for of the enzyme. Later studies in the same laboratory demonstrated that the enzyme has two binding sites for ATP. In the absence of acetylglutamate one site only is occupied, but only after binding of acetylglutamate to the enzyme is the second VYTP binding site active.

ii. Formation of Citrulline from Ornithine:


Citrulline is formed from carbamyl phosphate and ornithine by action of the liver enzyme, ornithine carbamyl transferase, also called ornithine transcarbamylase. The reaction in the liver is not reversible.

L-ornithine + carbamyl phosphate citruline + Pi

From kinetic studies on the purified enzyme (beef liver) Joseph and co-workers felt their data supported the hypothesis that the mechanism of their action involves binding of the two substrates (carbamyl phosphate and ornithine) simultaneously at different sites on the enzyme. They further suggested that the carbamyl phosphate binds almost entirely through the phosphate group.

iii. Formation of Arginine from Citrulline:


Arginine is formed in two reactions from citrulline. The first reaction (citrulline + succinate) is catalyzed by the liver enzyme arginosuccinate synthetase. It is ATP dependent, and with the formation of the new C—N bond in the guanidine group of arginosuccinate, water is removed and ATP is hydrolyzed.

citrulline + aspartate + ATP arginosuccinate + AMP + PPi + H2O

Ratner and associates, using purified enzyme and O18 labeling, showed that the ureido oxygen of citrulline is transferred to the adenylic acid moiety (AMP) of ATP. This suggested the interaction of ureido group and ATP and brought up the possibility of adenylo citrulline as an intermediate in this reaction.

The second reaction is catalyzed by arginine synthetase and involves the scission of arginosuccinate with the formation of a molecule each of arginine and fumaric acid.

arginosuccinate ⇌ L-arginine + fumaric acid

iv. Formation of Urea from Arginine:

Arginine is hydrolyzed to ornithine and urea by the enzyme arginase as shown in the equations. Arginase appears to occur only in the livers of animals that excrete urea; for example, it is not in the livers of birds, which excrete uric acid, but in the kidneys.

The two N atoms in a molecule of urea, one is derived from ammonia, through carbamyl phosphate, and the other from aspartic acid, through argin succinic acid.

Cohen and Brown estimate that the overall syntheses of urea from NH4+ and HCO3 through the ornithine cycle requires around 10 kcal of energy permol under standard conditions and pH 7.

NH4+ + HCO3 + aspartate± 2H2O + urea + fumarate– – + H+ (∆F°’298 = + 10.04 kcal)

The process is endergonic and requires that energy be supplied to make it go. Since three ATP are broken down in the reactions of urea synthesis, the overall process is strongly exergonic.

NH4+ + HCO3 + aspartate± + H2O + 3 ATP urea + fumarate– – + 2ADP + AMP + PP + Pi + H+ (∆F°’ = -13.15 kcal)

Term Paper # 4. Mechanism of Amino Group and Ammonia Inter-Conversion:

It appears that the L-amino acid oxidases of tissues do not have the quantitative capacity or breadth of specificity enabling them to account for the oxidative removal of the amino groups as NH3 from all the amino acids as a group. After NH3 is introduced as — NH2 groups into an amino acid, them the N is distributed throughout the other amino acids of the tissues by transamination reactions.

Also, the—NH2 groups of amino acids may be removed as NH3. It appears that a coupling of transamination reactions and the reversible oxidative deamination of glutamic acid to α-ketoglutaric acid and NH3 constitutes the mechanism that largely controls the removal of —NH2 groups from amino acids as NH3, and also “fixes” NH3 into amino acids as — NH2 groups.