Editing Urea cycle (section)

==Regulation==

===''N''-Acetylglutamic acid===
The synthesis of carbamoyl phosphate and the urea cycle are dependent on the presence of [[N-Acetylglutamic acid|''N''-acetylglutamic acid]] (NAcGlu), which [[allosterically]] activates [[Carbamoyl phosphate synthase|CPS1]]. NAcGlu is an obligate activator of carbamoyl phosphate synthetase.<ref>Kaplan Medical USMLE Step 1 Biochemistry and Medical Genetics Lecture Notes 2010, page 261</ref> Synthesis of NAcGlu by [[N-Acetylglutamate synthase|''N''-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 free [[amino acid]]s are elevated. So Glu not only is a substrate for NAGS 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 cycle enzymes other than [[Protein:ARG1|ARG1]] 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 to {{chem|NH|4|+}}, resulting in [[hyperammonemia]] (elevated [{{chem|NH|4|+}}]<sub>P</sub>).

Although the root cause of {{chem|NH|4|+}} toxicity is not completely understood, a high [{{chem|NH|4|+}}] puts an enormous strain on the {{chem|NH|4|+}}-clearing system, especially in the [[Human brain|brain]] (symptoms of urea cycle enzyme deficiencies include [[intellectual disability]] and [[lethargy]]). This clearing system involves [[Protein:GLUD1|GLUD1]] and [[Protein:GLUL|GLUL]], which decrease the [[2-oxoglutarate]] (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.<ref>{{Cite book |last=Voet |first=Donald |title=Biochemistry. Hauptbd. |last2=Voet |first2=Judith G. |date=1995 |publisher=Wiley |isbn=978-0-471-58651-7 |edition=2. rev. |location=New York |pages=734}}</ref>