Liver Physiology 4: Protein synthesis and the urea cycle in liver disease Flashcards
What happens to amino acids in the fed anabolic state?
- Amino acids surplus as there is a requirement for protein synthesis. They can then be metabolised to non-nitrogenous substances
E.g. glucose, glycogen or fatty acids
-Or they can be oxidised to generate ATP
What is the glucose-alanine cycle?
Trying to transport amino acids and carbon groups from muscles to the liver
Draw out a diagram and explain the glucose-alanine cycle
(ipad)
Need a certain amount of glucose in the blood for various processes otherwise muscle wasting occurs
Gone through glycogen stores
Glucagon and cortisol stimulate gluconeogenesis
The amino acids come from muscle proteins
Alanine is transported in the blood in large quantities
Transported into hepatocyte
Alanine aminotransferase (ALT) transaminates the amino group from glutamate
Produce pyruvate (an alpha-ketoacid)
Pyruvate can be a substrate in the TCA cycle to form glucose
The glutamate is recycled back and urea is formed
Glucose is then taken up by muscle cells and used to produce energy (glycolysis)
This makes pyruvate again and releases lactate as a by product
Pyruvate is then converted back to alanine
How is the glucose/alanine then removed from the liver?
- Moves carbon atoms of pyruvate
- Moves excess ammonia from muscle to liver as alanine.
- In the liver, alanine yields pyruvate – the starting block for gluconeogenesis
- Releases ammonia for conversion into urea
- Energetic burden of gluconeogenesis imposed on the liver rather than muscle
- Muscle ATP is then devoted to muscle contraction
What are the requirements for the urea cycle?
1 turn of the cycle:
- Consumes 3 ATP equivalents
- 4 high energy nucleotide PO4-
- The energy consumed by urea production is generated in the production of the cycle intermediates
What are the products of the urea cycle?
- Urea is the only compound generated
- All other components are recycled
How are the urea cycle and TCA cycle linked?
(ipad)
Through the aspartate-argininosuccinate shunt of the TCA cycle
Fumarate is produced in the cytosol by argininosuccinate lyase of the urea cycle
Enters the citric acid cycle in the mitochondrion
Converted to oxaloacetate (several steps)
Oxaloacetate accepts an amino group from glutamate (transamination)
Forms aspartate
Leave the mitochondrion
Donates its amino group to the urea cycle in the argininosuccinate synthetase reaction
Intermediates in the citric acid cycle are boxed
What is the mechanism of the urea cycle?
- One ammonia enters cycle by a transamination reaction to form glutamate (recycled by deamination)
- NH3 moves into the mitochondria and reacts with HCO3- (with ATP) to form carbamoyl phosphate (enzyme = carbamoyl phosphate synthase)
- Carbamoyl phosphate reacts with ornithine to form citrulline (enzyme = ornithine transcarbamylase)
4.Moves out into the cytoplasm through a transporter
5.Reacts with aspartate (and ATP) to form arginine succinate (enzyme = argininosuccinate synthase)
6.This breaks down into arginine and releases fumarate (enzyme = argininosuccinate lyase)
7.Arginine reacts with water to produce ornithine release urea (enzyme = arginase/ornithine aminotransferase)
- Ornithine then re-enters the mitochondria to continue the cycle
What enzyme aids the reaction of ammonia with HCO3- to form carbamoyl phosphate?
carbamoyl phosphate synthase
What enzyme aids reaction of ornithine and carbamoyl phosphate to form citrulline?
ornithine transcarbamylase
What enzyme aids the reaction of citrulline and aspartate to form arginine succinate?
argininosuccinate synthase
What enzyme aids the reaction of breaking down arginine and releases fumarate?
argininosuccinate lyase
What enzyme aids the reaction of arginine with water to produce ornithine releasing urea?
arginase/ornithine aminotransferase
What controls the cycle and how fast/slow it works?
- Via up/down regulation of the enzymes responsible
- Long term changes in the level of dietary protein can result in a 20-fold upregulation
- This could be seen in both high protein diets and starvation (protein breakdown)
