L16: Urea Cycle & Averting NH3 toxicity Flashcards
Fish are ___?
Ammonotelic (NH3-excreting)
Birds are___?
Uricotelic (Uric Acid-excreting)
Mammals are___?
Ureotelic (Urea-excreting)
Problem of making too much urea?
Gout
What is the principal site of NH3 detoxification?
The Liver; since high levels of ammonia in the blood are toxic, nitrogen is transported between organs in organic forms such as alanine, glutamate, glutamine, and urea.
Where are the enzymes located that the Urea cycle uses?
In both cytosolic and mitochondrial compartments
Overall stoichiometry for urea synthesis?
HCO3- + NH4+ + 3ATP + Aspartate + H2O -> UREA + 2ADP + 2Pi + AMP + PPi + Fumarate + 5H+
what does the urea cycle help do?
it helps to control body pH
Ornithine Transcarbamoylase rxn
Ornithine + Carrrbamoyl-P ->CITRULLINE
Argininosuccinate Synthase rxn
CITRULLINE + aspatate + ATP ->ARGININOSUCCINATE
Argininosuccinate lyase rxn
ARGININOSUCCINATE -> ARGININE + fumarate
Arginase rxn
ARGININE -> ORNITHINE + Urea
What stimulates the biosynthesis of all 5 urea cycle enzymes after a protein meal?
Glucagon
what amino acid is highly effective in stimulating glucagon release?
casein (milk protein)
What is the 1st committed step of the urea cycle?
CPS-1; it is allosterically activated by N-Acetylglutamate
When amino acid catabolism increases, glutamate levels rise and so does N-acetyl-glutamate. How?
N-Acetyl-glutamate synthase (NAGS)
NAGS rxn
Glutamate + Acetyl-CoA -> N-Acetyl-Glutamate + CoA
What is NAG?
it is the allosteric activator of CPS-1; it is needed to start the Urea Cycle
What are indicators of high AA content?
Glutamate and Arginine
Glu: substrate for NAG synthase
Arg: activates NAGS allosterically
What does NAG synthase deficiency result in?
Hyperammonemia
What is primary hyperammonemia?
it occurs when there is a mutation in the NAGS gene
What is secondary hyperammonemia?
it occurs when there are mitochondrial changes interfering with NAGS function
What can improve hyperammonemia?
the NAG analogue Carbamoylglutamate restores and improves Urea-Cycle function
What is the most common inherited urea cycle disorder?
Ornithine transcarbamoylase deficiency
OTC deficiency characteristics?
Clinical phenotype in affected males and heterozygous females ranges from neonatal hyperammonemic coma to asymptomatic results. In severely affected individuals, ammonia concentrations increase rapidly causing ATAXIA, lethargy, and death w/o rapid intervention
What causes episodic hyperammonemia?
arginine deficiency
Why aren’t children affected by arginine deficiency?
Because growth always requires arginine so it will be in abundance at the early growing stages of life.
What is an ammonia trap?
Liver Acinus
endothelial lining within the liver is ____?
fenestrated (full of openings exposing hepatocytes to blood)
What doe the fenestration in the lining within the liver do?
It permits rapid metabolite exchange between the liver and blood
What does the liver acinus prevent?
It prevents ammonia re-entry into circulation through differential utilization of ammonia
Periportal hepatocytes include ___?
glutaminase and urea cycle enzymes which have a LOW AFFINITY for NH3 (high capacity)
Perivenous scavenger cells include ___?
glutamine synthetase that has 40x HIGHER AFFINITY for NH3 (low capacity). GLN synthetase mope up NH3 that gets past the 1st segment (periportal hepatocytes)
