BIOC Lecture 8: Nitrogen III Flashcards
Is ammonia toxic?
Yes
Where is urea synthesised?
In the liver
What does the liver take up excess NH3 in the form of?
Alanine and glutamine from other tissues
Why is portal blood high in NH3?
GI absorption from bacterial metabolism
Is urea toxic?
No, it maintains N in a soluble non-toxic form
Urea vs ammonia solubility
Urea = soluble
Ammonia = non-soluble
Where is urea excreted?
Transported in blood to kidney for excretion
What does urea allow for the elimination of?
2 nitrogens
What is carbamoyl phosphate?
A high energy intermediate compound synthesised from bicarbonate and ammonia
Where does the ammonia in carbamoyl phosphate come from?
deamination of glutamine and glutamate
What does carbamoyl phosphate have to do with the urea cycle?
the first committed step in the urea cycle and serves as a critical nitrogen carrier that initiates the cycle
What is the carbamoyl phosphate reaction catalysed by?
Carbamoyl phosphate synthetase (CPS)
How does the carbamoyl phosphate reaction happen?
The enzyme CPS catalyzes the reaction where ammonia, carbon dioxide, and 2ATP combine to form carbamoyl phosphate
How is aspartate generated?
By transamination of glutamate and oxaloacetate
Where does the urea cycle occur?
First stage (steps 1 and 2) happens in the mitochondria
The rest of the cycle occurs in the cytoplasm/cytosol
What is the purpose of the urea cycle?
essential for nitrogen balance and detoxification in the body, converting potentially harmful ammonia into urea for safe excretion
What is the main point of regulation of the urea cycle?
Carbamoyl Phosphate Synthase activity
When is the urea cycle upregulated?
In conditions where there needs to be a high metabolism of amino acids also under starvation conditions
When can urea cycle activity be reduced?
With liver disease i.e. cirrhosis
How is carbamoyl phosphate synthase (CPS) regulated?
Allosterically regulated
What is allosteric regulation?
a protein’s function at one site is affected by the binding of a regulatory molecule to a separate, distinct site on the same protein
What molecule regulates CPS?
N-acetylglutamate
How does N-acetylglutamate (NAG) regulate CPS?
NAG binds allosterically to CPS I, enhancing its affinity for ATP and bicarbonate, thereby increasing its activity
How is N-acetylglutamate made?
from acetyl-CoA and glutamate in a reaction catalyzed by the enzyme N-acetylglutamate synthase (NAGS)
What characteristics do disorders of urea cycle enzymes have?
Variety of phenotypes - mainly neurological and all involve hyperammonemia
How are disorders of urea cycle enzymes treated?
- By dietary modification (decrease protein)
- Treat with amino acid-binding compounds
What is the most common urea cycle enzyme defect?
The OTC enzyme (step 2)
What is OTC?
Ornithine transcarbamylase (OTC) is an enzyme located in the mitochondria of liver cells. It catalyzes the second step of the urea cycle
What conversion happens during the 2nd stage of the urea cycle?
carbamoyl phosphate and ornithine to citrulline
How does the diagnosis of OTC defect range?
severe neonatal-onset forms to milder late-onset forms
What can NH4+ inhibit?
post-synaptic potentials
What do depletion of CAC intermediates cause?
Decreased ATP for brain function
What can ammonia toxicity in the brain lead to?
Swelling in brain cells
Why do brain cells swell?
Accumulation of glutamine in astrocytes increases osmotic pressure in the cerebral oedema
Ammonia toxicity in the brain causes inappropriate levels of what?
Neurotransmitters, GABA, glutamate, aspartate
What is the main nitrogen excretion product?
Urea
Other than urea, what is excreting in the kidney?
Ammonia NH4+
How is ammonia produced in the kidney?
By deamination of glutamine - reduces body acidity because the process removes protons
The metabolism of epithelial cells of kidney proximal tubules is designed to compensate for what?
metabolic acidosis
What is metabolic acidosis?
a decrease in blood pH due to an excess of acid or loss of bicarbonate
What is crucial in the bodies reaction to acidosis?
Glutaminase
How does glutaminase stop acidosis?
By converting glutamine to glutamate and ammonia, glutaminase facilitates the excretion of hydrogen ions as ammonium and indirectly contributes to bicarbonate production
