Theurea cycle (also known as theornithine cycle) is a cycle ofbiochemical reactions that producesurea (NH2)2CO fromammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are calledureotelic.
The urea cycle converts highly toxic ammonia to urea forexcretion.[1] This cycle was the first metabolic cycle to be discovered byHans Krebs andKurt Henseleit in 1932,[2][3][4] five years before the discovery of theTCA cycle. The urea cycle was described in more detail later on by Ratner and Cohen. The urea cycle takes place primarily in theliver and, to a lesser extent, in thekidneys.
Amino acid catabolism results in waste ammonia. All animals need a way to excrete this product. Mostaquatic organisms, orammonotelic organisms, excrete ammonia without converting it.[1] Organisms that cannot easily and safely remove nitrogen as ammonia convert it to a less toxic substance, such asurea, via the urea cycle, which occurs mainly in the liver. Urea produced by the liver is then released into thebloodstream, where it travels to thekidneys and is ultimately excreted inurine. The urea cycle is essential to these organisms, because if the nitrogen or ammonia is not eliminated from the organism it can be very detrimental.[5] In species includingbirds and mostinsects, the ammonia is converted intouric acid or itsurate salt, which is excreted insolid form. Further, the urea cycle consumes acidic waste carbon dioxide by combining it with the basic ammonia, helping to maintain a neutral pH.
The entire process converts two amino groups, one fromNH+ 4 and one fromaspartate, and a carbon atom fromHCO− 3, to the relatively nontoxic excretion producturea.[6] This occurs at the cost of four "high-energy"phosphate bonds (3 ATP hydrolyzed to 2ADP and oneAMP). The conversion from ammonia to urea happens in five main steps. The first is needed for ammonia to enter the cycle and the following four are all a part of the cycle itself. To enter the cycle, ammonia is converted tocarbamoyl phosphate. The urea cycle consists of four enzymatic reactions: onemitochondrial and threecytosolic.[1][7] This uses 6 enzymes.[6][7][8]
Before the urea cycle begins ammonia is converted to carbamoyl phosphate. The reaction is catalyzed bycarbamoyl phosphate synthetase I and requires the use of twoATP molecules.[1] The carbamoyl phosphate then enters the urea cycle.
Carbamoyl phosphate is converted tocitrulline. With catalysis byornithine transcarbamylase, the carbamoyl phosphate group is donated to ornithine and releases a phosphate group.[1]
Arginine is cleaved byarginase to form urea and ornithine. The ornithine is then transported back to the mitochondria to begin the urea cycle again.[1][7]
Since fumarate is obtained by removing NH3 from aspartate (by means of reactions 3 and 4), and PPi + H2O → 2 Pi, the equation can be simplified as follows:
Note that reactions related to the urea cycle also cause the production of 2NADH, so the overall reaction releases slightly more energy than it consumes. The NADH is produced in two ways:
One NADH molecule is produced by the enzymeglutamate dehydrogenase in the conversion of glutamate to ammonium andα-ketoglutarate.Glutamate is the non-toxic carrier of amine groups. This provides the ammonium ion used in the initial synthesis of carbamoyl phosphate.
The fumarate released in the cytosol is hydrated tomalate by cytosolicfumarase. This malate is then oxidized tooxaloacetate by cytosolicmalate dehydrogenase, generating a reduced NADH in the cytosol.Oxaloacetate is one of the keto acids preferred bytransaminases, and so will be recycled toaspartate, maintaining the flow of nitrogen into the urea cycle.
The two NADH produced can provide energy for the formation of 5ATP (cytosolic NADH provides 2.5 ATP with the malate-aspartate shuttle in human liver cell), a net production of two high-energy phosphate bond for the urea cycle. However, ifgluconeogenesis is underway in the cytosol, the latter reducing equivalent is used to drive the reversal of theGAPDH step instead of generating ATP.
The fate of oxaloacetate is either to produce aspartate via transamination or to be converted tophosphoenolpyruvate, which is a substrate forgluconeogenesis.
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence ofN-acetylglutamic acid (NAcGlu), whichallosterically activatesCPS1.[9][10] NAcGlu is an obligate activator of carbamoyl phosphate synthetase.[11] Synthesis of NAcGlu byN-acetylglutamate synthase (NAGS) is stimulated by both Arg, allosteric stimulator of NAGS, and Glu, a product in the transamination reactions and one of NAGS's substrates, both of which are elevated when freeamino acids are elevated. So Glu not only is a substrate for NAGS but also serves as an activator for the urea cycle.
The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in cycle enzymes other thanARG1 do not result in significant decreases in urea production (if any cycle enzyme is entirely missing, death occurs shortly after birth). Rather, the deficient enzyme's substrate builds up, increasing the rate of the deficient reaction to normal.
The anomalous substrate buildup is not without cost, however. The substrate concentrations become elevated all the way back up the cycle toNH+ 4, resulting inhyperammonemia (elevated [NH+ 4]P).
Although the root cause ofNH+ 4 toxicity is not completely understood, a high [NH+ 4] puts an enormous strain on theNH+ 4-clearing system, especially in thebrain (symptoms of urea cycle enzyme deficiencies includeintellectual disability andlethargy). This clearing system involvesGLUD1 andGLUL, which decrease the2-oxoglutarate (2OG) and Glu pools. The brain is most sensitive to the depletion of these pools. Depletion of 2OG decreases the rate ofTCAC, whereas Glu is both aneurotransmitter and a precursor toGABA, another neurotransmitter.[12]
The urea cycle and thecitric acid cycle are independent cycles but are linked. One of the nitrogen atoms in the urea cycle is obtained from the transamination of oxaloacetate to aspartate.[13] The fumarate that is produced in step three is also an intermediate in the citric acid cycle and is returned to that cycle.[13]
Urea cycle disorders are rare and affect about one in 35,000 people in theUnited States.[14]Genetic defects in the enzymes involved in the cycle can occur, which usually manifest within a few days after birth.[5] The recently born child will typically experience varying bouts ofvomiting and periods oflethargy.[5] Ultimately, the infant may go into acoma and developbrain damage.[5] New-borns with UCD are at a much higher risk of complications or death due to untimelyscreening tests andmisdiagnosed cases. The most common misdiagnosis isneonatal sepsis. Signs of UCD can be present within the first 2 to 3 days of life, but the present method to get confirmation by test results can take too long.[15] This can potentially cause complications such as coma or death.[15]
Urea cycle disorders may also be diagnosed in adults, and symptoms may includedelirium episodes,lethargy, and symptoms similar to that of astroke.[16] On top of these symptoms, if the urea cycle begins to malfunction in theliver, the patient may developcirrhosis.[17] This can also lead tosarcopenia (the loss of muscle mass).[17] Mutations lead to deficiencies of the various enzymes and transporters involved in the urea cycle, and cause urea cycle disorders.[1] If individuals with a defect in any of the six enzymes used in the cycle ingestamino acids beyond what is necessary for the minimum daily requirements, then the ammonia that is produced will not be able to be converted to urea. These individuals can experiencehyperammonemia, or the build-up of a cycle intermediate.
All urea cycle defects, except OTC deficiency, are inherited in anautosomal recessive manner. OTC deficiency is inherited as anX-linked recessive disorder, although some females can show symptoms. Most urea cycle disorders are associated withhyperammonemia, however argininemia and some forms of argininosuccinic aciduria do not present with elevated ammonia.
^abcdefghiNelson, David L.; Cox, Michael M.; Hoskins, Aaron A. (2021).Lehninger Principles of Biochemistry (8th ed.). New York: W. H. Freeman and Company.ISBN9781319228002.
^abcdTymoczko, John L.; Berg, Jeremy M.; Stryer, Lubert (2013).BIOCHEMISTRY A Short Course. W.H. Freeman and Company, New York. p. 529.ISBN978-1-4292-8360-1.
^Shigesada, Katsuya; Tatibana, Masamiti (1971). "Enzymatic synthesis of acetylglutamate by mammalian liver preparations and its stimulation by arginine".Biochemical and Biophysical Research Communications.44 (5):1117–1124.Bibcode:1971BBRC...44.1117S.doi:10.1016/S0006-291X(71)80201-2.PMID5160402.
^abMerritt, J. L.; Brody, L. L.; Pino, G.; Rinaldo, P. (2018). "Newborn screening for proximal urea cycle disorders: Current evidence supporting recommendations for newborn screening".Molecular Genetics and Metabolism.124 (2):109–113.doi:10.1016/j.ymgme.2018.04.006.PMID29703588.S2CID13858458.
^Judd, Sandra (2010).Genetic Disorders Sourcebook. Omnigraphics. p. 225.ISBN978-0-7808-1076-1.
Orange nodes:carbohydrate metabolism.
Violet nodes:photosynthesis.
Red nodes:cellular respiration.
Pink nodes:cell signaling.
Blue nodes:amino acid metabolism.
Grey nodes:vitamin andcofactor metabolism.
Brown nodes:nucleotide andprotein metabolism.
Green nodes:lipid metabolism.
