Amino Acid Degradation and the Urea Cycle* Flashcards
How proteins are degraded and amino acids are absorbed?
Proteolysis = the breakdown of protein to free amino acids. Protein begins digestion in the stomach.
Inputs into the pool are from dietary protein and proteolysis of cellular protein.
There are 5 separate active proton or sodium symporters (same ones in kidney). Disorders associated with defects in amino acid transport lead to increased levels of these amino acids in the urine, since the same transporters are used in the renal tubules.
Catabolism of amino acids. Metabolic breakdown of amino acids to urea and CO2 is a continuous drain. This is reduced during starvation, but is never turned off. Hence, there must be a daily intake of amino acids to replenish the pools (USRDA, 40-50g/day). From 12 to 20 grams of nitrogen (from amino acids) is excreted per day, principally as urea.
See pg. 273
What is Hartnup’ s disease?
Hartnup’s Disease - A defect in the transport system for neutral and aromatic amino acids from the gut and the renal tubules.
Symptoms: similar to pellagra (niacin B3 deficiency, 4D’s: Diarrhea, Dermatitis, Dementia, Death)
Treatment: administration of niacin
Diagnosis: Symptoms of pellagra with high levels of neutral and aromatic amino acids in
the urine and feces.
NOTE: Pellagra is a vitamin deficiency disease most commonly caused by a chronic lack of niacin (vitamin B3) in the diet. It can be caused by decreased intake of niacin or tryptophan.
What is cystinuria?
Cystinuria - A defect in the transport system for basic amino acids and cystine (a disulfide- linked dimer of cysteine) from the gut and the renal tubules.
Symptoms: cystine is relatively insoluble and forms crystals which can lead to urinary tract infections and kidney stones.
Treatment: fluids, and administration of the drug penicillamine, which reacts with cystine to form a significantly more soluble compound.
What are the abundant amino acids?
Glutamine and alanine are the most abundant amino acids in serum.
Alanine can be easily made from pyruvate. This is an efficient way for cells to send 3 carbon groups back to the liver to be easily converted into glucose while disposing of an NH4 group. Hence alanine is one of the most abundant amino acids in the blood.
What are the essential amino acids?
PVT TIM HALL
Phe, Val, Thr, Trp, Ile, Met, His, Arg, Leu, Lys
HISTIDINE - His ISOLEUCINE - Ile LEUCINE - Leu LYSINE - Lys METHIONINE - Met PHENYLALANINE - Phe THREONINE - Thr TRYPTOPHAN - Trp VALINE - Val ARGININE (For Growth) - Arg
NOTE:
All essentials in kid = same for adult
Cysteine - Cys becomes essential if methionine is low
Tyrosine - Tyr becomes essential if phenylalanine is low.
What is nitrogen balance?
If the total daily nitrogen loss in urine, skin, and feces are equal to the total daily nitrogen intake, then one is said to be in nitrogen balance, as most of us should be.
Positive balance: If nitrogen losses are less than intake, the subject is in positive nitrogen balance, as in children and convalescing adults.
Negative balance: If nitrogen losses are more than intake, the subject is in negative nitrogen balance, as in diseases involving wasting or starvation. Prolonged negative balance can be fatal if loss of body protein reaches about one-third of total body protein.
What are amino acids used for?
Amino acids are the structural units that make up proteins. They join together to form short polymer chains called peptides or longer chains called either polypeptides or proteins.
What is the Urea cycle?
The primary means by which amino acid-derived nitrogen is metabolized is through the sequential action of transaminases, glutamate dehydrogenase, and the urea cycle.
Ammonia release during catabolism of amino acids is toxic and must be constantly removed from the body. Since the constant excretion of ammonia in the urine would lead to drastic changes in blood pH, the body converts the free ammonia to urea, a readily soluble and easily excreted compound. Free ammonia can be picked up into carbamoylphoshate and glutamate and glutamine.
UREA CYCLE (mainly in the liver, some in the kidneys) Rxns:
- Carbamoylphosphate is formed from ammonia and CO2 by carbamoyl phosphate synthase.
- Citrulline is formed from Ornithine & Carbamoylphosphate by ornithine
transcarbamoylase. - Argininosuccinate is formed from citrulline and aspartate by arginosuccinate synthase. Aspartate is generated arises from the transamination of oxaloacetate by glutamate.
- Arginine and Fumarate are formed from the cleavage of argininosuccinate by arginosuccinase.
- Urea and Ornithine are formed from the cleavage of arginine by arginase.
See pg. 249
In a protein free diet, urea cycle enzymes decrease.
In a high protein diet or in starvation, urea cycle enzymes increase.
How do humans deal with and dispose of ammonia?
Free ammonia ion is highly poisonous so the body can move remove free NH + in three ways.
- Glutamate Dehydrogenase converts a-ketoglutarate to Glutamine
* Glutamine carries ammonia - glutamine synthetase turns glutamate into glutamine
- Carbamoyl Phosphate Synthase turns ammonia into Carbamoyl Phosphate
What is pyridoxyl phosphate?
Pyridoxal phosphate (vitamin b6): an essential cofactor for all transaminations.
Note: Pyridoxine functions as a cofactor in a number of reactions including: a) transaminations
b) decarboxylations
c) dehydration of ß-hydroxyamino acids
d) racemizations of α-amino acids e) removal of H2S from cysteine
What is a transamination reaction?
Transamination - The transfer of an amino group from an amino acid to an α-keto acid to form a new amino acid and a new keto acid catalyzed by transaminases or aminotransferases. Cofactor - Pyridoxal phosphate (vitamin b6): an essential cofactor for all transaminations.
Note: Pyridoxine functions as a cofactor in a number of reactions including: a) transaminations
b) decarboxylations
c) dehydration of ß-hydroxyamino acids
d) racemizations of α-amino acids e) removal of H2S from cysteine
See rxns pg. 244
How does the ammonia group in a protein I eat end up in urea?
Ammonia enters the urea cycle in the first step & indirectly in other steps & is eventually made into urea. Urea is water soluble, non protonatable, & inert.
What are metabolic diseases associated with the urea cycle?
See next slides
***Clinical signs for all urea cycle diseases is Ammonia Intoxication & assume all intelligence levels are normal unless stated otherwise.
Treatment of these metabolic diseases of urea cycle usually includes a low protein diet that is supplemented with arginine or citrulline since arginine usually becomes essential in these patients.
Also administration of sodium benzoate and sodium phenylacetate which bind up glycine and glutamine in adducts which are excreted in the urine can be helpful.
Serum ammonia is lowered since it must then be used to synthesize more of these nonessential amino acids thereby helping to lower the overall ammonia level.
Argininosuccinic aciduria
Defective enzyme: Argininosuccinase
Sign: Ammonia Intoxication
Blood: NH4 and Argininosuccinic Acid
Urine: Arginosuccinic Acid
Intelligence: Normal
Hyper-ammoniemia
Defective enzyme: Carbamoyl Phosphate Synthase
Sign: Ammonia Intoxication
Blood: High NH4
Urine: -
Intelligence: Normal
