Urea cycle

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Memorial plaque at the University Clinic Freiburg

The urea cycle (also ornithine or Krebs-Henseleit cycle ), discovered in 1932 at the Freiburg University Hospital by Hans Adolf Krebs and Kurt Henseleit , is a biochemical cascade in mammals that converts nitrogen-containing breakdown products, especially ammonium , into urea , which is then transferred the kidney is excreted. In birds and lizards living on land, uric acid is instead produced and excreted. Fish do not require any conversion of ammonia; in their case, the skin in direct contact with the water offers the simple route of osmosis.

The formation of urea takes place in the liver cells (hepatocytes) and to a lesser extent in the kidneys . The cycle is localized partly in the mitochondrion , partly in the cytosol , which is why transport proteins are necessary.

Urea cycle reactions

Scheme of the urea cycle. The reactions take place both in the mitochondrion (above) and in the cytosol (below). 1: L - ornithine ; 2: carbamoyl phosphate ; 3: L - citrulline ; 4: argininosuccinate ; 5: fumarate ; 6: L - arginine ; 7: urea ; L- Asp: L - aspartate ; CPS-1: carbamoyl phosphate synthetase I ; OTC: ornithine transcarbamylase ; ASA: argininosuccinate synthase ; ASL: argininosuccinate lyase ; ARG1: arginase 1

Cascade in the mitochondrion

Partial reactions of CPS-I ( catalyzed by carbamoyl phosphate synthetase I ):

  1. Hydrogen carbonates are phosphorylated and thus activated
    (1st ATP -dependent reaction)
  2. Accumulation of ammonia with splitting off of the phosphate residue , carbamate is formed .
  3. Carbamate is phosphorylated again and thus activated
    (2nd ATP-dependent reaction)

At the end there is carbamoyl phosphate, which is the entry product into the actual urea cycle in the cytosol. Both steps are catalyzed by the carbamoyl phosphate synthetase I .

Since there is no carrier to transport carbamoyl phosphate out of the mitochondrion, a detour via ornithine - citrulline must first take place. Both are non- proteinogenic alpha- L -amino acids, they differ precisely in the carbamate residue and carriers exist for them. Carbamoyl phosphate is thus transferred to ornithine with dephosphorylation, which creates citrulline. The reaction is catalyzed by ornithine transcarbamylase .

Citrulline is transported into the cytosol via the mitochondrial ornithine transporters 1 and 2 in the antiport to ornithine.

Cascade in the cytosol

Citrulline becomes argininosuccinate in the cytosol with the addition of L- aspartate ATP -dependently, catalysed by the enzyme argininosuccinate synthase (ASA).

Argininosuccinate reacts to form arginine by splitting off fumarate. The enzyme is argininosuccinate lyase (ASL).

In the last step, the enzyme arginase 1 (ARG1) catalyzes the reaction of arginine to ornithine. In this step, isourea is produced with the consumption of H 2 O, which is in equilibrium with urea.

Aspartate cycle

The aspartate cycle is used to recover aspartate from fumarate. The reactions correspond to those of the citric acid cycle . Fumarate is first converted into malate and then into oxaloacetate by the cytosolic enzymes ' fumarase ' and ' malate dehydrogenase ' . When malate is oxidized to oxaloacetate, NAD is reduced to NADH .

The oxaloacetate is transaminated with an α-amino acid to form L -aspartate. The α-amino acid used is usually glutamic acid , which is deaminated during transamination to the α-keto acid α-ketoglutarate . The catalyzing enzyme is ' aspartate aminotransferase '. Alternatively, oxaloacetate can also be introduced into gluconeogenesis , or via transporters anaplerotically into the citric acid cycle in the mitochondrion.

The malate obtained from fumarate by the cytolic fumarase can also be transported back to the mitochondrion via the malate-aspartate shuttle .

Energy balance

The sum equation of the urea cycle is:

During the synthesis of a urea molecule, four high-energy compounds are split (3 ATP and one pyrophosphate). This corresponds to the energy of 4 ATP molecules.

However, when aspartate is regenerated in the aspartate cycle, an NADH is created:

NADH is converted to ATP in the respiratory chain in the mitochondrion . One NADH here corresponds to 2.5 ATP.

Medical importance

Congenital defects in the enzymes of the urea cycle lead to an increase in the ammonium level in the blood ( hyperammonaemia ). In the urea cycle, an ammonium ion is incorporated into an amino acid and thus removed with each step. Therefore, the metabolic disorder is most severe when the early steps of the urea cycle, carbamoyl phosphate synthetase and ornithine transcarbamoylase are affected. Defects in later steps, argininosuccinate lyase and arginase, lead to less severe clinical pictures. The rise in the ammonium level leads to disorders of the brain function ( encephalopathy ) and even to coma . Before 1979 she was treated with exchange transfusion and peritoneal dialysis . Phenyl acetate and benzoate have also been given since 1979 . Phenyl acetate and benzoate react with glutamine and glycine to form phenacetylglutamine and N -benzoylglycine (hippuric acid) , which are excreted in the urine and thus remove nitrogen.

literature

  • Ulf Dettmer, Malte Folkerts, Eva Kächler, Andreas Sönnichsen: Intensive course in biochemistry . Elsevier, Munich 2005, ISBN 978-3-437-44450-0 .

Individual evidence

  1. ^ Tymoczko, John L. 1948-, Stryer, Lubert ,: Stryer Biochemie . 7th edition Spectrum, Heidelberg 2012, ISBN 978-3-8274-2988-9 , pp. 697 .
  2. ↑ Enns GM et al. : Survival after Treatment with Phenylacetate and Benzoate for Urea-Cycle Disorders . In: N Engl J Med . No. 356 , 2007, p. 2282-2292 , doi : 10.1056 / NEJMoa066596 ( abstract ).

Web links

Wikibooks: Biochemistry and Pathobiochemistry: Urea Cycle  - Learning and Teaching Materials