The reactions of the urea cycle.

The color scheme is as follows: enzymes, coenzymes, substrate names, inorganic molecules, Asp and urea's nitrogen that comes from it, NH₄⁺ and urea's nitrogen that comes from it, HCO₃^- and urea's carbon that comes from it

The urea cycle, also known as the ornithine cycle, is a cycle of biochemical reactions occurring in many animal organisms that produces urea from ammonia (NH₃). This cycle was the first metabolic cycle discovered (Krebs and Kurt Henseleit, 1932). In mammals, the urea cycle takes place only in the liver. Image File history File links Size of this preview: 520 × 599 pixel Image in higher resolution (623 × 718 pixel, file size: 29 KB, MIME type: image/png) I, the creator of this work, hereby release it into the public domain. ... Image File history File links Size of this preview: 520 × 599 pixel Image in higher resolution (623 × 718 pixel, file size: 29 KB, MIME type: image/png) I, the creator of this work, hereby release it into the public domain. ... Biochemistry is the study of the chemical processes and transformations in living organisms. ... Urea is an organic compound of carbon, nitrogen, oxygen and hydrogen, with the formula CON2H4 or (NH2)2CO. Urea is also known as carbamide, especially in the recommended International Non-proprietary Names (rINN) in use in Europe. ... Ammonia is a compound with the formula NH3. ... Sir Hans Adolf Krebs (August 25, 1900 – November 22, 1981) was a German, later British medical doctor and biochemist. ... The liver is an organ in some animals, including vertebrates (and therefore humans). ...

Function

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. Urea is an organic compound of carbon, nitrogen, oxygen and hydrogen, with the formula CON2H4 or (NH2)2CO. Urea is also known as carbamide, especially in the recommended International Non-proprietary Names (rINN) in use in Europe. ... This article or section is in need of attention from an expert on the subject. ... A genetic disorder, or genetic disease, is a condition caused by abnormal expression of one or more genes resulting in a clinical phenotype. ... Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. ... Liver failure is the final stage of liver disease. ... Hepatic encephalopathy is a condition (usually caused by liver cirrhosis and its resultant portal hypertension) where brain cells are damaged by a build-up of toxic substances in the blood. ...

Reactions

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 HCO₃^-, to relatively nontoxic excretion product, urea, at the cost of four "high-energy" phosphate bonds (3 ATP hydrolyzed to 2 ADP and one AMP). Orn is the carrier of these carbon and nitrogen atoms. Aspartic acid (Asp), also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Urea is an organic compound of carbon, nitrogen, oxygen and hydrogen, with the formula CON2H4 or (NH2)2CO. Urea is also known as carbamide, especially in the recommended International Non-proprietary Names (rINN) in use in Europe. ... Ornithine is an amino acid, whose structure is: NH2-CH2-CH2-CH2-CHNH2-COOH Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. ...

Reactions of cycle:

Summary reaction: Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... Carbamoyl phosphate is a molecule that is involved in ridding the body of excess nitrogen in the urea cycle, and also in the synthesis of pyrimidines. ... Adenosine diphosphate, abbreviated ADP, is a nucleotide. ... Carbamoyl phosphate synthase (EC 6. ... Carbamoyl phosphate is a molecule that is involved in ridding the body of excess nitrogen in the urea cycle, and also in the synthesis of pyrimidines. ... Ornithine is an amino acid, whose structure is: NH2-CH2-CH2-CH2-CHNH2-COOH Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. ... The chemical compound citrulline is an α-amino acid (AA). ... Ornithine transcarbamoylase(EC 2. ... The chemical compound citrulline is an α-amino acid (AA). ... Aspartic acid (Asp), also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... Arginosuccinic acid is a chemical compound that belongs to the class of the amino acids. ... Adenosine monophosphate, also known as 5-adenylic acid and abbreviated AMP, is a nucleotide that is found in RNA. It is an ester of phosphoric acid with the nucleoside adenosine. ... In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. ... Argininosuccinate synthetase is an enzyme that participates in the urea cycle, which is a sequence of chemical reactions that takes place in the cells of the liver. ... Arginosuccinic acid is a chemical compound that belongs to the class of the amino acids. ... Arginine (symbol Arg or R) is an α-amino acid. ... A fumarate is a salt or ester of fumaric acid. ... ASL (argininosuccinate lyase) is a human gene that makes the protein argininosuccinate lyase, one of the enzymes controlling a series of reactions called the urea cycle. ... Arginine (symbol Arg or R) is an α-amino acid. ... Ornithine is an amino acid, whose structure is: NH2-CH2-CH2-CH2-CHNH2-COOH Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. ... Urea is an organic compound of carbon, nitrogen, oxygen and hydrogen, with the formula CON2H4 or (NH2)2CO. Urea is also known as carbamide, especially in the recommended International Non-proprietary Names (rINN) in use in Europe. ... Arginase is a manganese-containing enzyme. ...

• 2 NH₃ + CO₂ + 4 ATP + aspartate → urea + fumarate + 4 ADP + 4 P_i

Note that reactions related to the urea cycle also causes the reduction of 2 NADH, so the urea cycle releases slightly more energy than it consumes. These NADH are produced in two ways: Ammonia is a compound with the formula NH3. ... Carbon dioxide is a chemical compound composed of one carbon and two oxygen atoms. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... Aspartic acid (Asp), also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Urea is an organic compound of carbon, nitrogen, oxygen and hydrogen, with the formula CON2H4 or (NH2)2CO. Urea is also known as carbamide, especially in the recommended International Non-proprietary Names (rINN) in use in Europe. ... Fumaric acid (IUPAC systematic name: 2-butenedioic acid), also called allomaleic acid, boletic acid or lichenic acid, is a colorless crystalline flammable carboxylic acid based on butene and molecular formula C4H4O4. ... Adenosine diphosphate, abbreviated ADP, is a nucleotide. ... Above is a ball-and-stick model of the inorganic hydrogenphosphate anion (HPO42−). Colour coding: P (orange); O (red); H (white). ... Nicotinamide adenine dinucleotide (NAD+) Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are two important coenzymes found in cells. ...

• One NADH molecule is reduced by the enzyme glutamate dehydrogenase in the conversion of glutamate to ammonium and a-ketoglutarate. Recall that 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 converted to malate by cytosolic fumarase. This malate is then converted to oxaloacetate by cytosolic malate dehydrogenase, generating a reduced NADH in the cytosol.

The two NADH produced can provide energy for the formation of 5 ATP, a net production of one high energy phosphate bond for the urea cycle. However, if gluconeogenesis is underway in the cytosol, the latter reducing equivalent is used to drive the reversal of the GAPDH step instead of generating ATP. Glutamate dehydrogenase is an enzyme, present in mitochondria, as are some of the other enzymes required for urea synthesis, that converts glutamate to α-Ketoglutarate, and vice versa. ... Malate (O−OC-CH2-CH(OH)-COO−) is the ionized form of malic acid. ... Fumarase is an enzyme involved in the Krebs Cycle that catalyzes the hydration (addition of H2O across a double bond) of Fumarate to L-malate (the natural optical isomer of a protein as apposed to the d isomer) Fumarase Deficiency In humans, Fumarase Deficiency is an enzyme irregularity that causes... Categories: Biochemistry stubs | EC 1. ... ATP may refer to: Chemistry/Biochemistry Adenosine triphosphate, the universal energy currency of all living organisms Companies Alberta Theatre Projects, a major Canadian theatre company. ... Pyruvic acid Oxaloacetic acid Phosphoenolpyruvate Fructose 1,6-bisphosphate Fructose 6-phosphate Glucose-6-phosphate Glucose Gluconeogenesis is the generation of glucose from non-sugar carbon substrates like pyruvate, lactate, glycerol, and amino acids (primarily alanine and glutamine). ... Glyceraldehyde 3-phosphate dehydrogenase (GAPDH or G3PDH, although this is not really correct) (EC 1. ...

Regulation

Alternate representation of urea cycle. Numbering is different from that presented above. Aqua oval is mitochondrion. CPS1 not displayed.

Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ...

NAcGlu

The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of NAcGlu, which allosterically activates CPS1. Synthesis of NAcGlu by NAGS, is stimulated by 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 free amino acids are elevated. So, Arg is not only a substrate for the urea cycle reactions but also serves as an activator for the urea cycle. N-Acetylglutamic acid (abbreviated NAcGlu) is biosynthesized from glutamic acid and acetyl-CoA by the enzyme N-acetylglutamate synthase. ... In biochemistry, allosteric regulation is the regulation of an enzyme or protein by binding an effector molecule at the proteins allosteric site (that is, a site other than the proteins active site). ... In chemistry, an amino acid is any molecule that contains both amino and carboxylic acid functional groups. ...

Substrate concentrations

The remaining enzymes of the cycle are controlled by the concentrations of their substrates. Thus, inherited deficiencies in the cycle enzymes other than ARG1 do not result in significant decrease in urea production (the total lack of any cycle enzyme results in death 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 to NH₄⁺, resulting in hyperammonemia (elevated [NH₄⁺]_P). Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. ...

Although the root cause of NH₄⁺ toxicity is not completely understood, a high [NH₄⁺] puts an enormous strain on the NH₄⁺-clearing system, especially in the brain (symptoms of urea cycle enzyme deficiencies include mental retardation and lethargy). This clearing system involves GLUD1 and GLUL, which decrease the 2OG and Glu pools. The brain is most sensitive to the depletion of these pools. Depletion of 2OG decreases the rate of TCAC, whereas Glu is both a neurotransmitter and a precursor to GABA, another neurotransmitter. [1](p.734) In animals, the brain, or encephalon (Greek for in the head), is the control center of the central nervous system. ... Mental retardation is a term for a pattern of persistently slow learning of basic motor and language skills (milestones) during childhood, and a significantly below-normal global intellectual capacity as an adult. ... Fatigue is a feeling of excessive tiredness or lethargy, with a desire to rest, perhaps to sleep. ... Oxoglutarate dehydrogenase (aka α-ketoglutarate dehydrogenase) is an enzyme complex most commonly known for its role in the citric acid cycle. ... Overview of the citric acid cycle The citric acid cycle (also known as the tricarboxylic acid cycle, the TCA cycle, or the Krebs cycle, after Hans Adolf Krebs who identified the cycle) is a series of chemical reactions of central importance in all living cells that use oxygen as part... Chemical structure of D-Aspartic Acid, a common Amino Acid neurotransmitter. ... Gaba may refer to: Gabâ or gabaa (Philippines), the concept of negative karma of the Cebuano people GABA, the gamma-amino-butyric acid neurotransmitter GABA receptor, in biology, receptors with GABA as their endogenous ligand Gaba 1 to 1, an English conversational school in Japan Marianne Gaba, a US model...

See also

• Citrullinemia
• Hyperammonemia
• Ornithine translocase deficiency

Citrullinemia is an inherited disorder that causes ammonia and other toxic substances to accumulate in the blood. ... Hyperammonemia is a metabolic disturbance characterised by an excess of ammonia in the blood. ... Ornithine translocase deficiency is a rare inherited disorder that causes ammonia to accumulate in the blood. ...

v • d • e  Urea Cycle Metabolic Pathway

L-citrulline Carbamoyl phosphate L-ornithine Pi L-aspartate Urea + ATP PPi + AMP H2O L-argininosuccinate Fumarate L-arginine

The reactions of the urea cycle. ... In biochemistry, a metabolic pathway is a series of chemical reactions occurring within a cell, catalyzed by enzymes, resulting in either the formation of a metabolic product to be used or stored by the cell, or the initiation of another metabolic pathway (then called a flux generating step). ... The chemical compound citrulline is an α-amino acid (AA). ... Carbamoyl phosphate is a molecule that is involved in ridding the body of excess nitrogen in the urea cycle, and also in the synthesis of pyrimidines. ... Ornithine is an amino acid, whose structure is: NH2-CH2-CH2-CH2-CHNH2-COOH Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. ... Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Aspartic acid, also known as aspartate, the name of its anion, is one of the 20 natural proteinogenic amino acids which are the building blocks of proteins. ... Urea is an organic compound of carbon, nitrogen, oxygen and hydrogen, with the formula CON2H4 or (NH2)2CO. Urea is also known as carbamide, especially in the recommended International Non-proprietary Names (rINN) in use in Europe. ... Image File history File links No higher resolution available. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... Image File history File links Biochem_reaction_arrow_special_1. ... Image File history File links Biochem_reaction_arrow_special_2. ... Image File history File links No higher resolution available. ... Adenosine monophosphate, also known as 5-adenylic acid and abbreviated AMP, is a nucleotide that is found in RNA. It is an ester of phosphoric acid with the nucleoside adenosine. ... Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... Image File history File links Fumarate_wpmp. ... Arginosuccinic acid is a chemical compound that belongs to the class of the amino acids. ... A fumarate is a salt or ester of fumaric acid. ... Arginine (symbol Arg or R) is an α-amino acid. ...

External links

• The chemical logic behind the urea cycle
• Basic Neurochemistry - amino acid disorders