The Urea Cycle Flashcards
Why is ammonia toxic?
NH3 is small, uncharged, and readily crosses the membranes where NH3 + H2O NH4+ + OH-. Thus raising intracellular pH. You are becoming more alkaline which is especially bad for the CNS. We keep a narrow range of pH for enzymes and protein structure. When you change the structure, you change the function.
Describe the urea cycle
Arginine is hydrolyzed to urea and ornithine. A cyclic process where ornithine is a regenerating substrate. 4 ATP equivalents are utilized. Enzymes distributed between the mitochondria and cytosol IN THE LIVER.
How does the body get rid of ammonia and CO2
The liver converts amino acids’ nitrogen to UREA and prevents ammonia toxicity.
What two things up-regulate urea cycle enzymes?
1) high protein diet “feed-forward” regulation
2) prolonged fasting
Describe how Arginine gives you Ornithine
Arginine (amino acid) uses the enzyme Arginase to deaminate using water. This gives you Urea and Ornithine. Urea is excreted. Ornithine picks up a piece of Citrulline and brings it back in and we cycle around to Argininosuccinate. Ornithine is where you start and finish.
Describe the urea cycle in the mitochondria
CO2+ H2O–>H2CO3 which spontaneously goes to bicarb and hydrogens. In the presence of carbonic anhydrase, this happens fast. In the presence of CPS-1, bicarb becomes Carbamoyl Phosphate. CPS-1 is an enzyme system using the CO linked with the ammonia plus the phosphate from one of the ATPs. You get the ammonia by way of glutamate dehydrogenase. Carbamoyl Phosphate condenses with Ornithine. The phosphate comes off using Ornithine Transcarbamoylase and gives you Citrulline. This synthesis is driven by the loss of phosphate from one of the ATPs. Citrulline is then taken into the cytosol for every Ornithin that comes in.
Describe the urea cycle in the cytoplasm
Citrulline is condensed again with Aspartate and becomes Arginosuccinate by way of the amino group of the Aspartate. We cleave off part to give us Arginine and the leftover carbon skeleton becomes Fumarate. Arginine becomes Urea and Ornithine using Arginase. To do this, you must have a constant supply of Aspartate. Fumarate can become Malate which can become OAA. Put an amino group of OAA using amino transferase and you regenerate Aspartate. The amino group from Aspartate is delivered to Citrulline.
What compound is an allosteric activator of CPS-1 and required for its activity?
N-Acetylglutamate
How is N-Acetylglutamate made?
Glutamate increases with AA catabolism and it joins with Acetyl-CoA using N-acetylglutamate synthetase.
What is the most obvious affected part of the body when there is a urea cycle disorder?
CNS signs (lethargy, seizures, hypotonia, coma). May also see respiratory distress due to alkalosis (free ammonia out there sucking up hydrogens=alkaline)
What is a connection between the portal veins and the caudal vena cava?
Portosystemic shunt
Describe a portosystemic shunt and why it causes problems
Not all of the blood is going to the liver from the colon like it should. Some goes to the vena cava and now you have lots of ammonia (TOXIC!) in the blood because the liver isn’t filtering it all.
Describe clinical signs of animals with a portosystemic shunt
Acute: CNS toxicity: anorexia, depression, and lethargy. Specifically, episodes of hyperactivity, head pressing, and circling, disorientation, temporary blindness, weakness, excess salivation, seizures, occasionally coma Chronic: vomiting, diarrhea, hematuria, tenesmus, PU/PD, fever, poor body condition, small stature,
Name the three types of shunts and what you know about them
1) Persistent patent ductus venosus
2) Genetic or congenital: rare
3) Acquired: cirrhosis, hepatits, neoplasia, other obstructive liver dz
Describe the two types of Rx for Portosystemic shunts
1) Surgery: tie/close off shunt-gradual is best to avoid portal hypertension
2) Low protein/high fiber diet with antibiotics
