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The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions occurring in many animals
that produces urea((NH2)2CO) from ammonia (NH3). This cycle was the first metabolic cycle discovered (Hans
Krebs and Kurt Henseleit, 1932). In mammals, the urea cycle takes place primarily in the liver, and to a lesser extent
in the kidney.

Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other
substance, like urea or uric acid, which are much less toxic. Insufficiency of the urea cycle occurs in some genetic
disorders (inborn errors of metabolism), and in liver failure. The result of liver failure is accumulation of
nitrogenous waste, mainly ammonia, which leads to hepatic encephalopathy.

 

The urea cycle consists of five reactions: two mitochondrial and three cytosolic. The cycle converts two amino
groups, one from NH4+ and one from Asp, and a carbon atom from HCO3í, to the relatively nontoxic excretion
product urea at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one
AMP). Ornithine is the carrier of these carbon and nitrogen atoms

Hyperammonemia (or hyperammonaemia) is a metabolic disturbance characterised by an excess of ammonia in the

blood. It is a dangerous condition that may lead to encephalopathy and death. It may be primary or secondary.

Ammonia is a substance that contains nitrogen. It is a product of the catabolism of protein. It is converted to the less
toxic substance urea prior to excretion in urine by the kidneys. The metabolic pathways that synthesise urea are
located first in the mitochondria and then into the cytosol. The process is known as the urea cycle, which comprises
several enzymes acting in sequence.






 

uV Primary hyperammonemia is caused by several inborn errors of metabolism that are characterised by
reduced activity of any of the enzymes in the urea cycle.
uV Decondary hyperammonemia is caused by inborn errors of intermediary metabolism characterised by
reduced activity in enzymes that are not part of the urea cycle (e.g. .Propionic acidemia, Methylmalonic
acidemia) or dysfunction of cells that make major contributions to metabolism (eg hepatic failure).

 



Treatment centers on limiting intake of ammonia and increasing its excretion. Dietary protein (a source of
ammonium) is restricted and caloric intake is provided by glucose and fat. Intravenous sodium phenylacetate and
sodium benzoate are pharmacologic agents commonly used as adjunctive therapy to treat hyperammonemia in
patients with urea cycle enzyme deficiencies.[1] Dodium phenylacetate and sodium benzoate can serve as alternatives
to urea for the excretion of waste nitrogen. Phenylacetate conjugates with glutamine to form phenylacetylglutamine,
which is excreted by the kidneys. Dimilarly, sodium benzoate reduces ammonia content in the blood by conjugating
with glycine to form hippuric acid, which is rapidly excreted by the kidneys.[2] A preparation containing sodium
phenylacetate and sodium benzoate is available under the trade name Ammonul.

Encephalopathy means disorder or disease of the brain.[1] In modern usage, encephalopathy does not refer to a
single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different
illnesses.
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In some contexts it refers to permanent (or degenerative)[2] brain injury, and in others it is reversible. It can be due to
direct injury to the brain, or illness remote from the brain. In medical jargon it can refer to a wide variety of brain
disorders with very different etiologies, prognoses and implications. For example, prion diseases, all of which cause
transmissible spongiform encephalopathies, are invariably fatal, but other encephalopathies are reversible and can be
caused by nutritional deficiencies, toxins, and several other causes.


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Citrullinemia: Citrullinemia is an inherited urea cycle disorder which causes toxic substances including ammonia to
build up in the blood. There are two main subtypes of Citrullinemia (I and II) which are caused by different genetic
abnormalities and result in different symptoms. Milder forms may present in childhood and rare late-onset forms
(adult-onset) may not cause symptoms until adulthood. More detailed information about the symptoms, causes, and
treatments of Citrullinemia is available below.

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uV Increased blood ammonia level - type I

uV Poor appetite - type I
uV ·istlessness - type I
uV Îomiting - type I
uV Deizures - type II
uV more symptoms...»

 


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uV Treatment generally involves sticking to a low protein diet

uV High ammonia levels in the blood can be managed by using intravenous sodium benzoate, sodium
phenylacetate and arginine
uV Devere cases may require hemodialysis to remove toxins from the blood
uV Oral sodium phenylbutyrate and arginine can be used as a long-term therapy
uV _egular blood tests are needed to monitor ammonia and amino acid levels



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Argininosuccinic aciduria is an inherited disorder that causes ammonia to accumulate in the blood. Ammonia, which
is formed when proteins are broken down in the body, is toxic if the levels become too high. The nervous system is
especially sensitive to the effects of excess ammonia.

Argininosuccinic aciduria usually becomes evident in the first few days of life. An infant with argininosuccinic
aciduria may be lacking in energy (lethargic) or unwilling to eat, and have poorly controlled breathing rate or body
temperature. Dome babies with this disorder experience seizures or unusual body movements, or go into a coma.
Complications from argininosuccinic aciduria may include developmental delay and intellectual disability.
Progressive liver damage, skin lesions, and brittle hair may also be seen.

Occasionally, an individual may inherit a mild form of the disorder in which ammonia accumulates in the
bloodstream only during periods of illness or other stress.


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Phases of the Krebs Cycle

After the glycolysis takes place in the cell's cytoplasm, the pyruvic acid molecules travel into the interior of the
mitochondrion. Once the pyruvic acid is inside, carbon dioxide is enzymatically removed from each three-carbon
pyruvic acid molecule to form acetic acid. The enzyme then combines the acetic acid with an enzyme, coenzyme A,
to produce Ê
 


, also known as acetyl CoA.

Once acetyl CoA is formed, the Krebs cycle begins. The cycle is split into eight steps, each of which will be
explained below.

Diagram of Krebs Cycle

Dtep 1

The acetic acid subunit of acetyl CoA is combined with oxaloacetate to form a molecule of Ê
. The acetyl
coenzyme A acts only as a transporter of acetic acid from one enzyme to another. After Dtep 1, the coenzyme is
released by hydrolysis so that it may combine with another acetic acid molecule to begin the Krebs cycle again.

Dtep 2

The citric acid molecule undergoes an isomerization. A hydroxyl group and a hydrogen molecule are removed from
the citrate structure in the form of water. The two carbons form a double bond until the water molecule is added
back. Only now, the hydroxyl group and hydrogen molecule are reversed with respect to the original structure of the
citrate molecule. Thus,   Ê
is formed.

Dtep 3

In this step, the isocitrate molecule is oxidized by a NAD molecule. The NAD molecule is reduced by the hydrogen
atom and the hydroxyl group. The NAD binds with a hydrogen atom and carries off the other hydrogen atom
leaving a carbonyl group. This structure is very unstable, so a molecule of CO2 is released creating ÊÊ

ÊÊ
.

Dtep 4

In this step, our friend, coenzyme A, returns to oxidize the alpha-ketoglutarate molecule. A molecule of NAD is
reduced again to form NADH and leaves with another hydrogen. This instability causes a carbonyl group to be
released as carbon dioxide and a thioester bond is formed in its place between the former alpha-ketoglutarate and
coenzyme A to create a molecule of   


complex.

Dtep 5

A water molecule sheds its hydrogen atoms to coenzyme A. Then, a free-floating phosphate group displaces
coenzyme A and forms a bond with the succinyl complex. The phosphate is then transferred to a molecule of GDP
to produce an energy molecule of GTP. It leaves behind a molecule of  Ê
.
Dtep 6

In this step, succinate is oxidized by a molecule of FAD (Flavin adenine dinucleotide). The FAD removes two
hydrogen atoms from the succinate and forces a double bond to form between the two carbon atoms, thus creating

 ÊÊ
.

Dtep 7

An enzyme adds water to the fumarate molecule to form ÊÊ
 The malate is created by adding one hydrogen
atom to a carbon atom and then adding a hydroxyl group to a carbon next to a terminal carbonyl group.

Dtep 8

In this final step, the malate molecule is oxidized by a NAD molecule. The carbon that carried the hydroxyl group is
now converted into a carbonyl group. The end product is ÊÊ
Ê
which can then combine with acetyl-
coenzyme A and begin the Krebs cycle all over again.

Dummary

In summary, three major events occur during the Krebs cycle. One GTP (guanosine triphosphate) is produced
which eventually donates a phosphate group to ADP to form one ATP; three molecules of NAD are reduced; and
one molecule of FAD is reduced. Although one molecule of GTP leads to the production of one ATP, the
production of the reduced NAD and FAD are far more significant in the cell's energy-generating process. This is
because NADH and FADH2 donate their electrons to an electron transport system that generates large amounts of
energy by forming many molecules of ATP.