urea cycle: averting NH3 toxicity Flashcards
excess nitrogen is constantly…
excreted from animals in a variety of metabolic forms
fish are…
ammonotelic (ie NH3-excreting)
birds are…
uricotelic(ie uric acid excreting)
mammals are…
ureotelic (ie urea-excreting); primarily make urea but some creatinine and uric acid; amount excreted varies; some of us make too much uric acid (gout)
where do the first two reactions of the urea cycle occur?
within the mitochondrial matrix
where do the last three steps of the cycle occur?
cytosol, which is the cell’s aq phase
what is transported back to the mitochondrial matrix?
ornithine
_____ is exported from the liver, entering circulation for uptake and excretion by the kidney
urea
Urea Transporters A and B
UT-A- exports urea from liver
UT-B- imports urea into kidney
what enzyme reactions in the urea cycle do you need to know? (draw them)
ornithine transcarbamoylase (mitochondria), argininosuccinate synthase (cytoplasm), argininosuccinate lyase (cytoplasm), and arginase (cytoplasm)
what do you absolutely need to know and draw out?
THE UREA CYCLE
what induces synthesis of urea cycle enzymes?
high protein diet
glucagon
pancreatic a-cell hormone that stimulates glucose synthesis as well as biosynthesis of urea cycle enzymes; certain AAs stimulate glucagon release and casein (main milk protein) is rich in those AAs; by reducing NH3, glucagon increases levels of a-keto-acids needed for glucose synthesis
indirect activation of urea cycle by glutamate and arginine
digestion of protein foodstuffs increases liver AA content, and transamination to a-KG increases liver glutamate levels; bc arginine undergoes little/no transamination, digestion of protein foodstuffs greatly increases liver arginine concentration; consequently, high levels of Gly & Arg trigger the synthesis of N-acetyl-glutamate, an essential activator of CPS-I, meaning that CPS-I is totally inactive in absence of N-acetyl-glutamate
N-acetyl-glutamate synthase
Glutamate+ Acetyl-CoA ->< N-Acetyl-Glutamate +CoA
NAG Synthase makes what?
N-acetylglutamate (NAG)= needed to jump-start Urea cycle
Glu and Arg are indicators of …
high AA intake/turnover; Glu is substrate for NAG synthase and Arg activates NAGS allosterically
NAG Synthase deficiency results in…
hyperammonemia
primary- NAGS gene deletion
secondary- any mitochondrial change that interferes with NAGS function
carbamoylglutamate activates CPS-I to start urea cycle pathway
endothelial lining within the liver is fenestrated, meaning…
full of openings, exposing hepatocytes to blood ( permits rapid metabolite exchange between liver and blood)
for all practical purpose, the hepatocytes are in direct contant with…
blood components
liver acinus prevents…
ammonia re-entry into circulation through differential utilization of ammonia
first segment of the liver acinus contains…
very little Glutamine Synthetase, but has lots of Glutaminase and high concentrations of urea cycle enzymes
CPS-I has ___________ for NH3, but urea removes any NH3 produced by Glutamate Dehydrogenase
low affinity
Peri-venous segment of the liver acinus
scavenger cells have 20x more glutamate transporters that capture bulk of excess glutamate; these cells also import any plasma NH3 that eluded the first segment
with 40x higher affinity than NH3 than CPS-I, __________________ has little trouble mopping up any NH3 that escapes the first segment; newly synthesized glutamine is exported to organs that invariably need it
glutamine synthetase
