Urea Cycle Flashcards
3 reasons for amino acid oxidation (catabolism)
- Proteins have a half-life…constant turnover of proteins…proteins broken down into amino acids and excess ones are degraded (since they cannot be stored)
- Excess amino acids from a high protein diet
- Prolonged fasting or starvation (or uncontrolled diabetes)…proteins are catabolized for energy
Fate of amino acids (3 general steps)
- Amino group is removed as ammonia…leaving the ketoacid carbon skeleton
- Ammonia is converted into urea in the urea cycle
- Ketoacid is oxidized, and converted to useful products
All transamination reactions are readily (?) and require what cofactor?
Reversible
Pyridoxal phosphate (PLP)
L-glutamate transamination
—> alpha-KG
Sources of NH4 from muscle
Alanine and glutamine
**glutamine is also a source from extrahepatic tissues
Excess amino acids are processed where? And what is their ultimate fate
In liver
Amino groups are transferred from amino acid through series of transamination and non-transamination reactions
Ultimately producing NH4 for the urea cycle
Amino group on alanine (from muscle)
Transferred to a-KG to make glutamate
Now alanine = pyruvate
Glutamine (from muscle and other tissues) —> …
Glutamine —> glutamate (donates NH4 to urea)
Then…
Glutamate —> a-KG (donates another NH4)
**both are examples of NON-transamination reactions
Cahill Glucose-Alanine Cycle
MUSCLE:
Protein —> Glu —> a-KG (and pyruvate —> Alanine)
LIVER:
Alanine and a-KG undergo transamination reaction
—> glutamate donates NH4
—> pyruvate —> gluconeogenesis —> glucose goes back to muscles to complete cycle
Alanine transaminase (ALT)
Enzyme for the transamination reaction between
Pyruvate/alanine & glutamate/a-KG
Occurs in muscle and liver in the Cahill glucose-alanine cycle
Ketogenic vs. glucogenic amino acids
Glucogenic = can be converted into glucose
Ketogenic = used to make FAs and ketone bodies
Cori Cycle
Uses muscle lactate (NOT alanine) to generate glucose
Lactate travels to the liver in the blood
Mitochondrial matrix
Regarding the urea cycle
Location for the input of most of the energy (in form of ATP)
Also this is the compartment where regulation occurs
Cytosol (urea cycle)
Where bulk of the reactions occur
Where urea is produced and then excreted in the urine
Production of carbomyl phosphate
MATRIX
NH4+ (from glutamate)
Combines with CO2 (from bicarbonate)
—> carbomyl phosphate = the activated molecule that enters the urea cycle
ENZYME: carbamoyl phosphate synthetase I (CPS I)
Uses 2 ATP
CPS I deficiency
Hyperammonemia
Seizures
Coma
Early death
Synthesis of citrulline
MATRIX
Carbamoyl phosphate condenses with ornithine
—> citrulline (releasing an inorganic phosphate)
ENZYME: ornithine transcarbamoylase
Citrulline then enters the cytosol
Ornithine transcarbamoylase (OT) deficiency
Hyperammonemia
If severe = coma and death
Signs = decrease citrulline and arginine concentrations
Increase of orotic acid in urine
Ornithine is analogous to what molecule in the CAC
OAA
Both are recycled at the end of the cycle
Synthesis of argininosuccinate
CYTOSOL
Aspartate condenses with citrulline
ENZYME: argininosuccinate synthetase
Argininosuccinate synthetase deficiency
Hyperammonemia
Citrullinemia
Common neurologic complications typicals of UCDs
Structural significance of argininosuccinate
(Fumarate)+(urea)+(ornithine)
Aspartate transaminase (AST)
Transamination reaction between
Glu/a-KG
Asp/OAA
Liver panel enzymes
AST and ALT
If activity is elevated = liver damage
Argininosuccinatase
Cleaves argininosuccinate into
Fumarate —> CAC
And
Arginine —> continues in urea cycle
Argininosuccinatase deficiency
Hyperammonemia
Argininosuccinate acidemia
Seizures
Common neuro shit for UCDs
Arginase
Cleaves arginine into UREA and ornithine
Urea —> excreted in urine
Ornithine —> re-enters the mitochondrial matrix to do another round of urea cycle
Arginase deficiency
Hyper-NH4
Argininemia
Slow growth
Mental retardation
N-acetylglutamate synthase
Condenses acetyl-CoA and glutamate —> N-acetylglutamate
Allosterically activated by ARGININE
N-acetylglutamate is an allosteric activator of CPS1 (produces carbamoyl phosphate)
Excess of glutamate and arginine (and other amino acids) —>
Stimulates urea cycle
N-acetylglutamate synthase deficiency
Hyper-NH4
Developmental delay
Mental retard
Seizures
Coma
Death
Hep A clinical presentation
Fatigue, loss of appetite, nausea, vomiting, pain in joints
Tender, enlarged liver
LAB = elevation in AST and ALT activity
Symptoms can worsen to neuro problems (toxicity levels of NH4…and liver damage is preventing urea production to get rid of NH4)
Hyperammonemia
Inability of the urea cycle to properly function
—> gradual decrease in CAC intermediates (a-KG, OAA, fumarate)
Which affects ATP production in the CNS
Lactulose
Medication to reduce NH4 levels
= nondigestible synthetic fructose-Gal disaccharide
Intestinal flora metabolize it to produce lactic and acetic acid —> acidifies colon
—> NH3 —> NH4 which isn’t absorbed as well
Reduces plasma NH4 levels
Benzoate and phenylbutyrate
Meds to reduce NH4
Benzoate metabolism uses glycine
Phenylbutyrate uses glutamine
Removes these amino acids from circulation
Cells then need to replace them with biosynthetic pathways…lowers nitrogen load
