2. Ammonia elimination Flashcards
What are the sources of ammonia in the ornithine cycle?
- Intestinal glutaminase, urease
- Hepatic transdeamination
- Hepatic purine nucleotide cycle
- Hepatic direct deamination (Ser, Gly, Thr, His, AA oxidases)
Ammonia and ammonium ion
-> Which one is readily absorbed?
Ammonia
How is the absorption of ammonia affected by pH?
Decreasing pH decreases the absorption of ammonia
Locations of high activity of purine nucleotide cycle
Muscle and brain
What is the net reaction of purine nucleotide cycle?
Asp deamination – fumarate – indirect deamination
What is the aim of purine nucleotide cycle?
Ammonia for Gln synthesis for the kidney.
Fumarate : anaplerotic for which cycle?
the citrate cycle
Asp amino group is funelled into the nucleotide (IMP)
=> Which substances are formed.
AMP and fumarate
Ornithine (Urea) cycle
-> Identify 1 - 5
Is Arg always converted into urea? Why?
Arg is not necessarily converted into urea, Arg can be used for other reactions as well (later).
If the cycle is for Arg synthesis (not for urea synthesis), e.g. in fast protein synthesis, then Arg must be suplied with ___
food.
What is the enzyme involving in Allosteric regulation of the ornithin cycle?
Carbamoylphosphate Synthetase by N-acetylglutamate
What is the localization of Allosteric regulation of the ornithin cycle? (Carbamoylphosphate Synthetase by N-acetylglutamate)
mitochondria
What is the activator of CPS1?
N-acetyl-glutamate
Production of N-acetyl-glutamate is stimulated by ____
dietary Arg (Arg) is also a direct precursor of urea in the cycle)
CPS1 activity increases both with ____ (2 CONDITIONS)
protein-rich food and in starvation
Glucagon prevents the exit of ___ from the mitochondria.
N-acetylglutamate
Does allosteric regulation of the ornithin cycle have product inhibition?
No
Fumarate produced by the urea cycle can regenerate ____ via enzymes involved in the tricarboxylic acid (TCA) cycle
aspartate
Fumarate produced by the urea cycle can regenerate aspartate via enzymes involved in ____ (which cycle?)
the tricarboxylic acid (TCA) cycle
Which organ produces Arg?
Gut-kidney axis
Citrulline synthesis in __ (which organ?)
the intestine
Arg is produced from citrulline in ___ (which organ?)
the kidney
What happen to production of Arg if there is small intestine or kidney damage?
less Arg is synthesized than needed. Arg - essential AS.
Long term regulation (transcriptional and regulation with sirtuin-deacetilation)
- Fasting, protein rich food, but also high cortisol levels and cAMP increases the transcription of urea cycle enzymes
- Sirtuins: NAD dependent deacetylases: Deacetylated CPS, OTC - active
- SIRT-5 deacetylates and activates CPS, SIRT-3 – OTC.
The role of SIRT-5
SIRT-5 deacetylates and activates CPS, SIRT-3 – OTC.
What is the deffect in type I hyperammonemia?
deffect: carbamoyl phosphate synthetase
What is the deffect in type II hyperammonemia?
deffect: ornithine transcarbamoylase
What are transporter deficiencies in Hyperammonemia?
+ transporter deficiencies – ORNT1 (Orn/Citr exchanger), CITRlN (Asp/Glu exchanger)
Name of these syntheses?
Metabolism of ammonia in the periportal and pericentral hepatocytes
Periportal hepatocytes: urea cycle eliminates ___ (percentage) of NH3
70%
Metabolism of ammonia in the periportal and pericentral hepatocytes
Periportal hepatocytes: urea cycle eliminates 70% of NH3
=> rest of NH3 will become ___
substrate of Gln synthetase
What are the 2 possibilities of incorporation of free ammonia in the liver?
1: Ornithine cycle CP synthetase reaction (ATP) 2: Glutamine synthetase (ATP)
Special role of Gln in the metabolism
___ (g?) Gln/day is metabolized
100
What are the sources of Gln?
- Food: only 50% gets into the circulation
- Muscle: 80g
Ammonia is transported in the form of ___ in the blood
Gln
____ (percentage) of the total amino acids in the blood is Gln
25%
Glutamine
1. Mainly from ___
2. Mainly serve for ___
- Muscle, degradation of BBCA
- Energy
Ammonia elimination in the brain
The high ammonia cc. (hyperammonemia) puts a huge strain on ____ (which reactions?), especially in the brain.
ammonia-eliminating reactions
What are The possibilities of elimination in the brain?
Glutamine synthetase
Glutamate dehydrogenase
Ammonia elimination in the brain
α-Ketoglutarate is used up to reduce ___
The ammonia, the citrate cycle is exhausted, the ATP level is low: fatigue, coma
What are some therapies for Brain oedema?
- Osmolytes against brain oedema
- Inhibit N-Absorption in the gut – Lactulose ( not digested disacharid, gives protons)
- Antibiotics to inhibit bacteria in the gut
- Synthetic products to eliminate NH3: biotransformation
- Arginine or Ornithine to complete the cycle.
What happen during acidosis?
the ornithine cycle slows down, less HCO3 is used, NH3 – NH4+.
– CPS1 reaction is inhibited, NAG synthesis and glutaminase slow down, more ammonia
enters the pericentral hepatocytes. More Gln comes out of the liver - into the kidneys.
