Urea Cycle

▪ Urea is the end product of protein metabolism (amino acid
metabolism). The nitrogen of amino acids, converted to ammonia (as

described above), is toxic to the body. It is converted to urea and
detoxified. As such, urea accounts for 80-90% of the nitrogen
containing substances excreted in urine.
▪ Urea is synthesized in liver and transported to kidneys for excretion
in urine. Urea cycle is the first metabolic cycle that was elucidated by
Hans Krebs and Kurt Henseleit (1932), hence it is known as Krebs-
Henseleit cycle. The individual reactions, however, were described in
more detail later on by Ratner and Cohen.
▪ 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.
▪ One molecule of ammonia condenses with CO2 in the presence of
two molecules of ATP to form carbamoyl phosphate.
▪ The reaction is catalysed by the mitochondrial enzyme carbamoyl
phosphate synthetase-I (CPS-I).
▪ CPS-I reaction is the rate-limiting step in urea formation.
▪ It is irreversible and allosterically regulated.

▪ The second reaction is also mitochondrial.
▪ The carbamoyl group is transferred to the NH2 group of ornithine by
ornithine transcarbamoylase (OTC)
▪ The citrulline leaves the mitochondria and further reactions are taking
place in cytoplasm.
▪ Citrulline is neither present in tissue proteins nor in blood; but it is present
in milk
▪ One molecule of aspartic acid adds to citrulline forming a carbon to
nitrogen bond which provides the 2nd nitrogen atom of urea.

Argininosuccinate synthetase catalyses the reaction. This needs
hydrolysis of ATP to AMP level, so two high energy phosphate bonds
are utilized. The PPi is an inhibitor of this step.
▪ Argininosuccinate is cleaved by argininosuccinate lyase (argininosuccinase) to
arginine and fumarate.
▪ The enzyme is inhibited by fumarate. But this is avoided by the cytoplasmic
localization of the enzyme. The fumarate formed may be funnelled into TCA cycle
to be converted to malate and then to oxaloacetate to be transaminated to
aspartate.
▪ Thus the urea cycle is linked to TCA cycle through fumarate. The 3rd and 4th steps
taken together may be summarized as:
▪ Citrulline + aspartate → Arginine + fumarate

▪ The final reaction of the cycle is the hydrolysis of arginine to urea and
ornithine by arginase.
▪ The ornithine returns to the mitochondria to react with another
molecule of carbamoyl phosphate so that the cycle will proceed.

Thus, ornithine may be considered as a catalyst which enters the
reaction and is regenerated.
The overall reaction may be summarized as:
▪ NH3 + CO2 + Aspartate → Urea + fumarate
▪ During these reactions, 2 ATPs are used in the 1st reaction.
▪ Another ATP is converted to AMP + PPi in the 3rd step, which is equivalent to 2 ATPs.
▪ The urea cycle consumes 4 high energy phosphate bonds.
▪ However, fumarate formed in the 4th step may be converted to malate.
▪ Malate when oxidised to oxaloacetate produces 1 NADH equivalent to 2.5 ATP
▪ So net energy expenditure is only 1.5 high energy phosphates.
▪ The urea cycle and TCA cycle are interlinked, and so, it is called as "urea bicycle".
▪ 1. Coarse Regulation
▪ The enzyme levels change with the protein content of diet. During starvation, the
activity of urea cycle enzymes is elevated to meet the increased rate of protein
catabolism.
▪ 2. Fine Regulation
▪ The major regulatory step is catalyzed by CPS-I where the positive effector is N-
acetyl glutamate (NAG). It is formed from glutamate and acetyl CoA (Fig. 14.14).
Arginine is an activator of NAG synthase
▪ 3. Compartmentalization
▪ The urea cycle enzymes are located in such a way that the first two enzymes are in
the mitochondrial matrix. The inhibitory effect of fumarate on its own formation is
minimized because argininosuccinate lyase is in the cytoplasm, while fumarase is
in mitochondria

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▪ Urea is the end product of protein metabolism (amino acid

metabolism). The nitrogen of amino acids, converted to ammonia (as

other from aspartate. Carbon atom is supplied by CO2. Urea

two molecules of ATP to form carbamoyl phosphate.

▪ The reaction is catalysed by the mitochondrial enzyme carbamoyl

phosphate synthetase-I (CPS-I).

▪ CPS-I reaction is the rate-limiting step in urea formation.

▪ It is irreversible and allosterically regulated.

▪ The carbamoyl group is transferred to the NH2 group of ornithine by

ornithine transcarbamoylase (OTC)

▪ Citrulline is neither present in tissue proteins nor in blood; but it is present

nitrogen bond which provides the 2nd nitrogen atom of urea.

arginine and fumarate.

▪ The enzyme is inhibited by fumarate. But this is avoided by the cytoplasmic

taken together may be summarized as:

▪ Citrulline + aspartate → Arginine + fumarate

▪ The ornithine returns to the mitochondria to react with another

molecule of carbamoyl phosphate so that the cycle will proceed.

▪ NH3 + CO2 + Aspartate → Urea + fumarate

▪ During these reactions, 2 ATPs are used in the 1st reaction.

▪ The urea cycle consumes 4 high energy phosphate bonds.

▪ However, fumarate formed in the 4th step may be converted to malate.

▪ Malate when oxidised to oxaloacetate produces 1 NADH equivalent to 2.5 ATP

▪ So net energy expenditure is only 1.5 high energy phosphates.

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