Urea cycle week 4 Flashcards
What organ is ammonia specifically toxic to and why?
What can lead to insufficiency of the urea cycle? What disease results from accumulation of ammonia?
Ammonia isvery toxic, especially to the CNS! It’s concentration in the blood is normally very low (alpha-ketoglutarate is used by aminotransferases to accept an amino group and form glutamate. this takes away alpha-ketoglutarate from the TCA cycle-less energy for the brain). Organisms that can’t efficiently remove ammonia must usually convert it to some other substance, such as urea (via urea cycle) or uric acid, which is much less toxic. Some genetic disorders (inborn errors of metabolism) and liver failure lead to insufficiency of the urea cycle. The result of liver failure is accumulation of nitrogenous waste, primarily ammonia, which leads to hepatic encephalopathy (global brain dysfunction).
What 2 aa does ammonia primarily travel in the blood as? Where do these aa go and how is the ammonia released?
Ammonia travels to the liver from other body tissues, primarily in the form of alanine and glutamine. It is released from AA in the liver by a series of transamination and deamination reactions.
In what organ does the urea cycle occur? What is the equation for the urea cycle? (what and how many molecules are needed?)
The urea cycle (also known as the ornithine cycle) produces urea (NH2)2 CO from ammonia (NH3).
**The urea cycle takes place only in the liver. **
2 Ammonia + carbon dioxide + 3ATP —> urea + water + 2 ADP + 1 AMP
Where do the 2 amine groups come from for urea production? What enzyme is involved?
How may acidosis affect urea production?
One amine group comes from oxidative deamination of glutamate (glutamate dehydrogenase) and one comes from aspartate, and a carbon atom from CO2 (or bicarbonate, depending upon blood chemistry) to yeild the relatively nontoxic excretion product, urea.
If in acidosis and need HCO3- to neutralize acid, not as much urea is made.
What molecule is the carrier of C and N atoms and has the same carbons present before and after the cycle?
How many steps is the urea cycle? What is the cellular localization of the steps?
Ornithine is the carrier of these carbon and nitrogen atoms and the same carbons are present in ornithine before and after the cycle.
The urea cycle consists of five reactions, two mitochondrial and three cystolic.
Explain the 5 steps of the urea cycle. Indicate the enzymes that catalyze each step and where ATP is needed.
- In the mitochondria, ammonium condenses with CO2 to form carbamoyl phosphate. catalyzed by carbamoyl phosphate synthetase I (CPS I). Requires 2 ATP.
- Carbamoyl phosphate reacts with ornithine to form citrulline. catalyzed by ornithine transcarbamoylase (OTC). Citrulline moves to the cytosol for the remaining reactions.
- Aspartate and citruline react to form argininosuccinate. catalyzed by arginosuccinate synthetase (ASS). Requires 1 ATP.
- Arginosuccinate is cleaved to fumarate and arginine. catalyzed by arginosuccinate lyase (ASL)
- Arginine is hydrolyzed to urea and ornithine. catalyzed by arginase (ARG 1).
attached is slide 122 of notes
Where is urea transported for excretion?
A small amount of urea diffused from the blood into the intestine. What enzyme reacts with urea in the intestine? What is produced and where do the products go?
Urea is transported by the blood to the kidney for excretion. The urea excreted each day by a healthy adult accounts for ~90% of the nitrogenous excretory products. A small amount of urea diffuses from the blood into the intestine and is cleaved by bacterial urease into NH3 and CO2 which can then be put back into the urea cycle .
What is the rate limiting step of urea synthesis? How is the enzyme that catalyzes this step regulated?
short term regulation: rate limiting step: formation of carbamoyl phosphate by CPS I. CPS I requires N-acetyl-glutamate, an allosteric activator. acetyl CoA+glutamate: N-acetyl-glutamate. The enzyme that synthesizes N-acetyl-glutamate is regulated positively allosterically by arginine.
How is the urea cycle regulated long term?
What is the key association btwn the TCA cycle and the urea cycle?
- Urea cycle enzymes are further induced after a high- protein diet is consumed for 4 or more days.
- The key association between the urea cycle and the TCA cycle is that one of the urea N is supplied to the urea cycle in the form of aspartate from the TCA cycle intermediate, oxaloacetate (AST).
What molecule is a widely used measure of the kidneys’ ability to excrete nitrogenous wastes? What is elevated levels of this parameter called?
In what situations may this parameter be elevated? (hint: 3)
Blood urea nitrogen (BUN): is a widely used measure of the kidney’s ability to excrete nitrogenous waste. Changes in BUN levels may be elevated (uremia):
• in both acute and chronic renal failure.
• with congestive heart failure which leads to a low blood pressure and subsequent reduced filtration rates through the kidneys.
• due to urinary tract obstructions.
Pts with liver disease cannot detoxify ammonia. How may the subsequent hepatic encephalopathy be treated? (how are ammonia levels reduced?)
Patients with severe liver disease can’t detoxify ammonia. The subsequent hepatic encephalopathy can be treated with pharmaceuticals which can reduce ammonia by either:
-increasing bacterial assimilation of ammonia
-reducing deamination of nitrogenous
compounds.
In what situation/disease does bacterial urease become clinically important and why?
In kidney failure, plasma urea levels are elevated resulting in greater transfer of urea from the blood into the gut. This is where the bacterial urease becomes clinically important by converting even more urea into NH3 and CO2 thus raising the plasma level of NH3.
What does a hereditary deficiency of CPS I lead to?
A hereditary deficiency of carbamoyl phosphate synthetase (CPS ) results in an inability for nitrogenous wastes (ammonia) to be metabolized via the urea cycle. Ammonia levels rise in these patients, leading to brain damage, coma, and/or death if strict dietary control is not followed.
How does cirrhosis affect the urea cycle?
Cirrhosis of the liver, characterized by fibrous scar tissue and regenerative nodules, interferes with the enzymes that produce carbamoyl phosphate in the first step of the urea cycle.
