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Urea Cycle




Urea is much less toxic than ammonia; therefore, organisms that cannot easily and quickly remove ammonia usually have to convert it to some other substance, like Urea or Uric Acid . Insufficiency of the urea cycle occurs in some Genetic Disorder s ( Inborn Errors Of Metabolism ), and in Liver Failure . The result in liver failure is accumulation of nitrogenous waste, mainly ammonia, which leads to Hepatic Encephalopathy .


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 carier of these carbon and nitrogen atoms.

Reactions of cycle:
:(''1'') ATP + HCO3- + NH4+Carbamyl Phosphate + 2 ADP + Pi (catalyzed by CPS1 )

:(''2'') Carbamyl Phosphate + OrnithineCitrulline + Pi (catalyzed by OTC )
:(''3'') Citrulline + Aspartate + ATPArgininosuccinate + AMP + PPi (catalyzed by ASS )
:(''4'') ArgininosuccinateArg + Fumarate (catalyzed by ASL )
:(''5'') Arg + H2O → Ornithine + Urea (catalyzed by ARG1 )

Summary reaction:


REGULATION


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 , 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 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 , 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. {Link without Title} ''(p.734)''


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