Can we produce glucose from fumarate?

The urea cycle - a biochemical cycle

Table of Contents

The breakdown of proteins

As part of the constant breakdown and build-up of structural proteins in the body, free amino acids are constantly accumulating, which the body can either reuse to synthesize new proteins or break them down. The amino group can be split off from the respective amino acid in two ways. The transfer of the amino group to an α-keto acid, which then becomes an amino acid, is more common. This is known as Transamination. It is much rarer Deamination, releasing the amino group as ammonia (NH3). Any transamination needed Pyridoxal phosphate (PALP) as a cofactor (coenzyme). This is the active form of vitamin B.6, which often plays a role in the reactions of the amino acid metabolism.

The transport of nitrogen in the blood

Via the process of the Transamination In the periphery, predominantly cells of the skeletal muscles, nitrogen atoms are bound to amino acids in the form of an amino group. These can then be released into the blood and reach the liver. Amino acids are particularly suitable here, the synthesis of which can take place from intermediate products of major metabolic pathways, for example the citrate cycle.

This is a central amino acid in nitrogen transport Glutamate, which is produced in the peripheral cells of the body by the transfer of an amino group to α-ketoglutarate. This then serves as a substrate for the transamination or can take up another amino group and is then used as a Glutamine released into the blood. In the human body, glutamine is the amino acid with the highest plasma concentration and is mainly used to transport nitrogen to the kidneys but also to the liver. In the kidney, glutamine is actually broken down to form ammonia. However, this serves to neutralize acids around urine and is secreted in the area of ​​the proximal tubule.

Another representative of these amino acids is Alanine. It represents the most important transport mechanism of nitrogen from the skeletal muscles to the liver. Alanine is produced in the peripheral cells by the glutamate transferring its amino group to pyruvate. The alanine is then used in the liver cell to form aspartate from oxaloacetate. After releasing the amino group, pyruvate remains, which can then be metabolized in the mitochondria or fed into gluconeogenesis. If, in the latter case, glucose gets back into the muscles, which is oxidized there to pyruvate, a cycle is created. Here one also speaks of Alanine cycle.

urea is the product of the urea cycle and is released into the bloodstream by the liver. It is a water-soluble substance that contains two nitrogen atoms. Along with glutamine, it is the most important molecule in nitrogen transport in the blood.

The urea cycle in the liver

In humans, the actual urea cycle takes place exclusively in the liver. If the nitrogen atoms reach the liver via the amino groups of the three amino acids described above via the blood, they can be bound there in the form of urea to an easily excreted end product. This is extremely important because it causes the formation of ammonia (NH3), which has a neurotoxic effect in particular, is prevented. The reactions of the urea cycle take place in the hepatocytes of the liver, the first two of them within the mitochondrion, i.e. intramitochondrially and the following ones in the cytosol of the cell. The following is an overview of the individual reaction steps of the urea cycle, which can best be understood using a schematic representation of the cycle.

Note: The urea cycle only takes place in the liver.

Image: “Urea Cycle” by Phil Schatz. License: CC BY 4.0

Reaction steps of the urea cycle

1. Formation of carbamyl phosphate (mitochondrion)

Catalyzed by the enzymeCarbamoyl phosphate synthetase 1 arises in the mitochondrial matrix from ammonia (NH3) and Co2 a molecule Carbamoyl phosphate. This pacemaker reaction of the urea cycle consumes two molecules of ATP. The first nitrogen atom in urea thus comes from the ammonia produced during the breakdown of amino acids or purine bases. The resulting carbamyl phosphate is strongly polar so that it cannot pass through the mitochondrial membrane.

2. Formation of citrulline (mitochondrion)

In the second reaction step, the carbamoyl residue of the carbamoyl phosphate is transferred to the amino acid ornithine. This amino acid is non-proteinogenic, so the body does not use it for the synthesis of proteins. In this reaction made by the Ornithine carbamoyl transferase is catalyzed, arises Citrulline. Citrulline is also non-proteinogenic and what remains in this step is phosphate. For the next reaction step, the citrulline has to cross the mitochondrial membrane in order to get into the cytosol of the hepatocyte. This is mediated by a translocator in the membrane, which exchanges citrulline and ornithine in the antiport.

3. Formation of argininosuccinate (cytosol)

The next reaction takes place in the cytosol, in the Argininosuccinate is synthesized from citrulline and aspartate. The aspartate contains an amino group that binds to the citrulline. This is where the second nitrogen atom enters the urea cycle. The enzyme responsible is that Argininosuccinate synthetase. The reaction requires energy that comes from the hydrolysis of ATP to AMP. So here two high-energy bonds are split.

4. Splitting of argininosuccinate into arginine and fumarate (cytosol)

The argininosuccinate is then used by the Argininosuccinate lyase catalyzes to the proteinogenic amino acid Arginine and split fumarate. The further use of the by-product fumarate will be explained later.

5. Hydrolysis of arginine (cytosol)

In the last reaction of the urea cycle, the arginine is released from the Arginase hydrolyzed and split off the entire urea group. This creates both urea, as well as the amino acid ornithine, which is channeled back into the mitochondrial matrix via the mitochondrial membrane in exchange with citrulline. There it is available again for the second reaction step, so that the cycle of the urea cycle closes at this point. The resulting urea molecule is released into the bloodstream by the hepatocytes via special transport proteins in the cell membrane.

Regeneration of the fumarate

During the urea cycle, argininosuccinate is formed in the cytosol of the hepatocyte when argininosuccinate is broken down Fumarate. This is subsequently called by the enzymes Fumaraseand malate dehydrogenase via the intermediate step Malate to Oxaloacetate transformed. Even if these steps also occur in the citrate cycle, it must be taken into account that these reactions take place in the cytosol. The oxaloacetate can be transaminated back to aspartate as a substrate, so that a metabolic cycle results here too. This is known as Aspartate cycle. Since fumarate is also an intermediate product of Citric acid cycle is, it can also be smuggled into this.

Note: Part of the urea cycle takes place in the mitochondrial matrix and part in the cytosol of the hepatocyte.

Energy balance of the urea cycle

The synthesis of urea is a comparatively energy-intensive process, which the body accepts in order to safely excrete the nitrogen. Above all, this means keeping the plasma level of ammonia as low as possible. Specifically, there are two reaction steps in the urea cycle in which energy is required from the cleavage of high-energy bonds. The Carbamoyl phosphate synthetase 1 in the mitochondrion requires 2 molecules of ATP, which are hydrolyzed to ADP. The consumes in the cytosol Argininosuccinate synthetase only 1 molecule of ATP, which however is hydrolyzed twice to AMP and pyrophosphate. The pyrophosphate is very quickly converted into 2 molecules of phosphate in the cytosol. In total, the urea cycle contains 3 molecules of ATP and the cleavage of 4 high-energy bonds.

Note: Even if only 3 molecules of ATP appear, 4 high-energy bonds are hydrolyzed in the urea cycle.

Regulation of the urea cycle

The pacemaker reaction that determines urea synthesis is that of the Carbamoyl phosphate synthetase 1 catalyzed the first reaction of the urea cycle. The enzyme is produced through allosteric binding of N-acetyl glutamate. This molecule increases in amount in proportion to the concentration of glutamate and acetyl-CoA. This is a meaningful connection since a high concentration of glutamate reflects a high occurrence of substrate and acetyl-CoA a sufficient amount of energy-rich substances. If both conditions are met, the liver increases its urea synthesis accordingly.

Note: The key enzyme in the urea cycle is carbamoyl phosphate synthetase 1.

The elimination of urea

The liver produces around 30g of urea every day via the urea cycle and releases it into the blood. This value can be significantly higher or lower, depending on the protein content of the food, as the body only breaks down excess amino acids. Urea is readily soluble in water and can thus reach the kidneys in dissolved form via the circulation, where it is excreted in the urine. Urea makes up the largest proportion of nitrogen-containing compounds in the urine.

Since urea is glomerularly filtered by the kidneys and partially reabsorbed, it is a suitable laboratory medical parameter for kidney function. The concentration of urea in the blood is one of the so-called Kidney retention parameterswhich, among other things, show increased values ​​with impaired kidney function. This is also known as when the normal values ​​with diverse clinical symptoms are exceeded Uremia. However, the fluctuations with altered protein intake must be taken into account, which can make the parameter unreliable.

Urea cycle disorders

When the physiological functioning of the urea cycle in the liver is impaired, this leads to the accumulation of ammonia in the blood. This increased plasma level (> 250 μg / dl) of ammonia or ammonium, the ionized form of ammonia, is known as Hyperammonaemia. Depending on the form and age of manifestation, the neurotoxic ammonia unfolds its harmful effects in the brain and can lead to a variety of neurological symptoms, irreversible brain damage and ultimately death. Pathophysiologically, this is probably due to a swelling of the astrocytes due to increased glutamine levels and the resulting formation of brain edema. The causes usually lie in an acquired or congenital disorder of the liver function.

Urea cycle defects

A possible cause for the insufficient function of the hepatic urea cycle is a defect in one of the catalyzing enzymes. The following 6 known enzyme defects are described:

Affected enzymeEnzyme defect
Carbamoyl phosphate synthetase I.CPS deficiency
N-acetyl glutamate synthetaseNAGS deficiency
Ornithine transcarbamylaseOTC shortage
Argininosuccinate synthaseASA deficiency (citrullinemia type I)
Argininosuccinate lyaseASL deficiency (arginine succinic acid disease)
Arginase-1 deficiencyHyperargininemia

All of these metabolic disorders are inherited as an autosomal recessive trait, with the exception of the OTC deficiency, which is inherited recessively via the X chromosome. The incidence in the United States is approximately 1 in 8,000. The age of onset can vary widely and occur in every phase of life. Acute courses in newborns are particularly life-threatening. In advanced adolescence and adults, diffuse neurological symptoms such as headache, poor concentration, tremors of the hands ("flapping tremor"), vomiting and lethargy are common. If left untreated, these enzyme defects can lead to mental retardation and death.

The diagnosis is based on a laboratory-medically confirmed high ammonia plasma level and can be supplemented by genetic tests. Acute treatment often consists of diuresis; in the long term, it is imperative to ensure a diet that is low in protein or low in nitrogen. The only curative option is liver transplantation.

Cirrhosis of the liver

Another common cause is an advanced loss of liver function, for example due to cirrhosis of the liver. The liver's lack of detoxification capacity leads to increased ammonia levels. If neurological symptoms occur in addition, one speaks of one hepatic encephalopathy. Depending on the clinical manifestation, this is divided into grades 1-4, with grade 4 corresponding to coma (coma hepaticum). Therapeutically, various measures can be used to try to lower the ammonia concentration in the blood, but the only curative option in the case of advanced liver cirrhosis is liver transplantation.

Popular exam questions about the urea cycle

The solutions can be found below the references.

1. Which statement about the urea cycle is incorrect?

  1. Ornithine is exchanged in antiport with citrulline via the mitochondrial membrane.
  2. For the synthesis of argininosuccinate, two high-energy bonds are split.
  3. Citrulline is formed in the cytosol.
  4. The arginase catalyzes hydrolysis.
  5. The formation of argininosuccinate occurs in the cytosol.

2. Which of the following enzymes determines the activity of the urea cycle?

  1. Argininosuccinate synthetase
  2. Arginase
  3. Glutamate pyruvate transaminase
  4. Malate dehydrogenase
  5. Carbamoyl phosphate synthetase 1

3. What is not a typical symptom of hyperammonaemia?

  1. Agitation
  2. Loss of sensitivity in the lower extremity
  3. Somnolence
  4. Coarse trembling of the hands
  5. Poor concentration


Rassow et al: Duale series Biochemie, Thieme Verlag, 2nd edition

Löffler, Petrides: Biochemistry and Pathobiochemistry, Springer Verlag, 9th edition

Kirchner, Mühlhäußer: BASICS Biochemie, Elsevier Verlag

MEDI-LEARN: Biochemistry, 4th edition

Solutions to the questions: 1C 2E 3B

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