Urea cycle

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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 (NH₄⁺). This cycle was the first metabolic cycle discovered (Krebs and Kurt Henseleit, 1932).

1 Function
2 Reactions
3 Regulation
- 3.1 NAcGlu
- 3.2 Substrate concentrations
4 See also
5 External links

[edit] 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.

[edit] 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.

Reactions of cycle:

Step	Reactant	Product	Catalyzed by	Location
1	2ATP + HCO₃^- + NH₄⁺	carbamoyl phosphate + 2ADP + P_i	CPS1	mitochondrial
2	carbamoyl phosphate + ornithine	citrulline + P_i	OTC	mitochondrial
3	citrulline + aspartate + ATP	argininosuccinate + AMP + PP_i	ASS	cytosolic
4	argininosuccinate	Arg + fumarate	ASL	cytosolic
5	Arg + H₂O	ornithine + urea	ARG1	cytosolic

Summary reaction:

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

[edit] Regulation

Image:Urea-Cycle scheme 2006-01.svg

[edit] 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.

[edit] 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 GLUD1 and GLUL, which decrease the 2OG and Glu pools. The brain is most sensitive to the depletion of these pools. Depletion of 2OG decreses the rate of TCAC, whereas Glu is both a neurotransmitter and a precursor to GABA, another neurotransmitter. [1](p.734)