Urea Cycle Disorders

The Urea Cycle

The cell is a very complex structure that contains components performing many activities necessary for survival. In order to understand the function of the urea cycle, it is important to have an understanding of where the functions of the urea cycle occur. The urea cycle takes place in the liver. The steps in the urea cycle occur in two places in the cells of the liver: the mitochondria and the cytosol within the cytoplasm.

Urea Cycle

The yellow area of the cell is the cytoplasm. The outer blue wall is the plasma membrane.
Used with permission from: Thibideau, GA, Patton, KI: Anatomy and Physiology, ed 4, St. Louis, 1999, Mosby

The first three steps in the urea cycle (NAGS, CPS and OTC) occur in the mitochondria of the cell. The mitochondria contain the metabolic pathways involved in the metabolism of the carbohydrates, lipids and amino acids. The special pathways involving heme and urea synthesis are also located in the mitochondria. It generates most of the cell's ATP that provides the energy for the metabolic pathways to occur.

The last three steps of the urea cycle (ASS, ASL, and ARG) occur in the cytosol. Cytosol is the aqueous solution that makes up the cytoplasm. It contains thousands of enzymes involved in intermediate metabolism and ribosomes making proteins.

NAGS - N-acetylglutamine Synthase
CPS - Carbamyl Phosphate Synthetase
OTC - Ornithine Transcarbamylase
ASS - Argininosuccinate Synthetase
ASL - Argininosuccinate Synthase Lyase
ARG - Arginase

Chemcycle10

Chemcycle

Download Chemcycle in pdf format 10

Chemical Reactions in the Urea Cycle 11
Description of Individual Steps	Enzyme	Cellular Compartment
N-acetylglutamine is an allosteric activator. It is synthesized from acetyl-CoA and glutamate.	N-Acetylglutamate Synthase (NAGS)	Mitochondria
First N is aquired via condensation and activation of NH4+ and HCO3 to form Carbamyl Phosphate Carbamyl Phosphate synthetase requires this allosteric activator to commit the cycle to occur	Carbamyl Phosphate Synthetase I (CPSI)	Mitochondria
Transfers carbamyl group to ornithine to make citrulline The energy for the reaction producing citrulline is provided by Carbamyl Phosphate	Ornithine Transcarbamylase (OTC)	Mitochondria (ornithine is transported into the mitochondria; citrulline is transported out; transport is driven by electrochemical gradient)
Second N is aquired via condensation of citrulline's uredio (urea containing) group and aspartate amino group to form argininosuccinate note: Urea is now assembled	Argininosuccinic Synthetase (ASS)	Cytosol
Fumarate is eliminated leaving arginine	Argininosuccinate Lyase (ASL)	Cytosol note: the fumarate that is produced is converted back to asparate. The first two reactions are the same as in the TCA cycle, but they occur in the cytosol
Hydrolysis of arginine to yield UREA and regenerate Ornithine	Arginase (ARG)	Cytosol

N=nitrogen
NH4+=Ammonia
HCO3=bicarbonate

Download Chemical Reactions in the Urea cycle in pdf format

References:

10. Paselk, Richard “Nitrogen metabolism- urea cycle”
http://www.humboldt.edu/~rap1/C431.F01/C431Notes/C431n14Dec.htm (May 4,2005)

11. Univeristy of Alaska Fairbanks, “Amino acid metabolism and the urea cycle” http://www.uaf.edu/chem/451f00D/HW31.htm (May 4, 2004)