Document 5

TOPIC: UREA CYCLE
Introduction……………………………………………………….……………………………1
Synthesis of carbamoyl phosphate………………...…………………………………………...2
Formation of citrulline…………………………………………………………………………3
Synthesis of arginosuccinate…………………………………………………………………...4
Cleavage of arginosuccinate……………………………………………………………………5
Formation of urea………………………………………………………………………………6
Regulation of urea cycle………………………………………………………………………. 7
Integration between urea cycle and TCA cycle………………………………………………...8
Urea cycle disorders……………………………………………………………………………9
References……………………………………………………………………………………...10
Figure 1: Urea cycle.
Urea cycle is the primary metabolic pathway involved in the removal of nitrogenous waste
produced from breakdown of protein and other nitrogen containing compounds.
The urea cycle is also known as the ornithine cycle. Urea is the end product of protein
metabolism. The nitrogen of amino acids, converted to ammonia is toxic to the body. It is
converted to urea and detoxified. It is a cycle of biochemical reactions that produces urea from
ammonia. This cycle occurs in ureotelic organisms. The urea cycle converts highly toxic
ammonia to urea for excretion. Urea cycle is the first metabolic cycle that was described by
Hans Krebs and Kurt Henseleit in 1932, hence it is known as Krebs-Henseleit cycle.
Urea has two amino (NH2) groups, one derived from NH3 and the other from aspartate. Carbon
atom is supplied by CO2. Urea synthesis is a five-step cyclic process, with five distinct enzymes.
The first two enzymes are present in mitochondria while the rest are localized in cytosol.
1. Synthesis of carbamoyl phosphate
Figure no 2: Formation of carbamoyl phosphate.

Carbamoyl phosphate synthase I (CPS I) of mitochondria catalyses the condensation of NH4 +
ions with CO2 to form carbamoyl phosphate. This step consumes two ATP and is irreversible,
and rate-limiting. CPS I require N-acetylglutamate for its activity. Another enzyme, carbamoyl
phosphate synthase II (CPS II) involved in pyrimidine synthesis is present in cytosol. It accepts
amino group from glutamine and does not require N-acetylglutamate for its activity.
2. Formation of citrulline
Figure no 3: Synthesis of citrulline.

Citrulline is synthesized from carbamoyl phosphate and ornithine by ornithine
transcarbamoylase. Ornithine is regenerated and used in urea cycle. Therefore, its role is
comparable to that of oxaloacetate in citric acid cycle. Ornithine and citrulline are basic amino
acids. Citrulline produced in this reaction is transported to cytosol by a transporter system.
3. Synthesis of arginosuccinate
Figure no 4: Formation of arginosuccinate.
Arginosuccinate synthase condenses citrulline with aspartate to produce arginosuccinate. The

second amino group of urea is incorporated in this reaction. This step requires ATP which is
cleaved to AMP and pyrophosphate (PPi). The latter is immediately broken down to inorganic
phosphate (Pi).
4. Cleavage of arginosuccinate
Figure no 5: Arginosuccinate cleavage give arginine and fumaric acid.

Arginosuccinase cleaves arginosuccinate to give arginine and fumarate. Arginine is the
immediate precursor for urea. Fumarate liberated here provides a connecting link with TCA
cycle, gluconeogenesis etc.
5. Formation of urea
Figure no 6: Urea formation.
Arginase is the fifth and final enzyme that cleaves arginine to yield urea and ornithine. Ornithine,
so regenerated, enters mitochondria for its reuse in the urea cycle. Arginase is activated by Co2 +
and Mn2+. Arginase is mostly found in the liver, while the rest of the enzymes of urea cycle are
also present in other tissues. For this reason, arginine synthesis may occur to varying degrees in
many tissues. But only the liver can ultimately produce urea.
Overall reaction and energetics:

The urea cycle is irreversible and consumes 4 ATP. Two ATP are utilized for the synthesis of
carbamoyl phosphate. One ATP is converted to AMP and PPi to produce arginosuccinate which
equals to 2 ATP. Hence 4 ATP are actually consumed.
NH4+ + CO2 + Aspartate + 3ATP →Urea+ Fumarate + 2 ADP + 2 Pi + AMP + PPi
Regulation of urea cycle:

The first reaction catalysed by carbamoyl phosphate synthase I (CPS I) is rate-limiting reaction
or committed step in urea synthesis. CPS I is allosterically activated by Nacetylglutamate
(NAG). The rate of urea synthesis in liver is correlated with the concentration of N-
acetylglutamate. High concentrations of arginine increase NAG. The consumption of a protein-
rich meal increases the level of NAG in liver, leading to enhanced urea synthesis. Carbamoyl
phosphate synthase I and glutamate dehydrogenase are localized in the mitochondria. They
coordinate with each other in the formation of NH3, and its utilization for the synthesis of
carbamoyl phosphate. The remaining four enzymes of urea cycle are mostly controlled by the
concentration of their respective substrates.
Integration between urea cycle and TCA cycle:
Figure no 7: The production of fumarate in urea cycle is the most important integrating point with TCA cycle.
Fumarate is converted to malate and then to oxaloacetate in TCA cycle. Oxaloacetate undergoes transamination to
produce aspartate which enters urea cycle. Here, it combines with citrulline to produce arginosuccinate.
Urea cycle is linked with TCA cycle in three different ways. This is regarded as bicyclic
integration between the two cycles.
1. The production of fumarate in urea cycle is the most important integrating point with TCA
cycle. Fumarate is converted to malate and then to oxaloacetate in TCA cycle. Oxaloacetate
undergoes transamination to produce aspartate which enters urea cycle. Here, it combines with
citrulline to produce arginosuccinate. Oxaloacetate is an important metabolite which can
combine with acetyl CoA to form citrate and get finally oxidized. Oxaloacetate can also serve as
a precursor for the synthesis of glucose.
2. ATP (12) are generated in the TCA cycle while ATP (4) are utilized for urea synthesis.
3. Citric acid cycle is an important metabolic pathway for the complete oxidation of various
metabolites to CO2 and H2O. The CO2 liberated in TCA cycle (in the mitochondria) can be
utilized in urea cycle.
Metabolic disorders of urea cycle:

Metabolic defects associated with each of the six enzymes of urea cycle have been reported are
given below. All the disorders invariably lead to a build-up in blood ammonia, leading to
toxicity. Other metabolites of urea cycle also accumulate which, however, depends on the
specific enzyme defect. The clinical symptoms associated with defect in urea cycle enzymes
include vomiting, lethargy, irritability, ataxia and mental retardation.
Figure no 8: Disorders of urea cycle.
References:
 Tymoczko, John L.; Berg, Jeremy M.; Stryer, Lubert (2013). BIOCHEMISTRY A Short
Course. W.H. Freeman and Company, New York. p. 529.
 Mew, Nicholas Ah; Pappa, Maria Belen; Gropman, Andrea L. (2015-01-01), Rosenberg,
Roger N.; Pascual, Juan M. (eds.), "Chapter 57 - Urea Cycle Disorders", Rosenberg's
Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition),
Boston: Academic Press, pp. 633–647.
 Atkinson, Daniel (September 20, 1991). "Functional Roles of Urea in
Vertebrates". Physiological Zoology (2 ed.). Los Angeles: The University of Chicago
Press. 65 (2): 243–267.
 Kaplan Medical USMLE Step 1 Biochemistry and Medical Genetics Lecture Notes
2010, page 261.

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TOPIC: UREA CYCLE

1. Synthesis of carbamoyl phosphate

Figure no 2: Formation of carbamoyl phosphate.

Figure no 3: Synthesis of citrulline.

Figure no 4: Formation of arginosuccinate.

Arginosuccinate synthase condenses citrulline with aspartate to produce arginosuccinate. The

Figure no 5: Arginosuccinate cleavage give arginine and fumaric acid.

Figure no 6: Urea formation.

Overall reaction and energetics:

Regulation of urea cycle:

Integration between urea cycle and TCA cycle:

Metabolic disorders of urea cycle:

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