Urea cycle

Function

Organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like 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.

Reactions

The urea cycle consists of five reactions - two Orn is the carrier of these carbon and nitrogen atoms.

Reactions of cycle:

Step	Reactant	Product	Catalyzed by	Location
1	2carbamoyl phosphate + 2ADP + Pi	CPS1	mitochondria
2	OTC	mitochondria
3	ASS	cytosol
4	Arg + fumarate	ASL	cytosol
5	urea	ARG1	cytosol

Overall energy requirement:

• AMP

Overall equation of the urea cycle:

• 2 H

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:

• One NADH molecule is reduced by the enzyme glutamate dehydrogenase in the conversion of glutamate to ammonium and 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 aspartate, maintained the flow of nitrogen into the urea cycle.

The two NADH produced can provide energy for the formation of 5 GAPDH step instead of generating ATP.

The fate of oxaloacetate is either to produce aspartate via oxidative deaminatin or to be converted to phosphoenyl pyruvate, which is a substrate to glucose.()

An excellent way to memorize the Urea Cycle is to remember the phrase "Ordinarily Careless Crappers Are Also Frivolous About Urination." The first letter of each word corresponds to the order in which reactants are combined to give products or intermediates that break apart as one progresses through the cycle.

Regulation

N-Acetylglutamic acid

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.

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).

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 GABA, another neurotransmitter. [1](p.734)

Pathology

Diseases associated with the urea cycle include:

• Citrullinemia
• Hyperammonemia
• Ornithine translocase deficiency
• N-Acetylglutamate synthase deficiency

Additional images

v • d • e Urea cycle enzymes
Main cycle	Carbamoyl phosphate synthase I - Argininosuccinate synthetase - Argininosuccinate lyase - Arginase
Regulatory/transport	N-Acetylglutamate synthase - Ornithine translocase