Ammonia Flashcards
What does the removal of an amino group of amino acid create?
- NH3
- a-keto acid
Can amino acids be kept in a storage form?
No
What is the first step of amino acid breakdown?
Removal of nitrogen by transamination
What is ammonia converted to in the liver?
Urea
What is the amino group passed to in the first step of amino acid breakdown?
a-ketoglutarate
- Creating glutamate
What does the amino acid become when an amino group is removed?
a-keto acid
What is the function of aminotransferases?
Transfer nitrogen from amino acids to glutamate
What do aminotransferases require as a cofactor?
B6
Give to examples of aminotransferases which may also be used as liver function tests?
- ALT - Alanine aminotransferase
- Aspartate aminotransferase (AST)
What does AST take an amino acid from and what does it give it to to yield?
AST takes an amino group from aspartate and transfers it to a-ketoglutarate to create Glutamate
What does aspartate become after it has been deaminated by AST?
Oxaloacetate
What are the 2 methods by which nitrogen can be transferred from glutamate to liver for excretion in urea cycle?
- Glutamine synthesis
2. Alanine cycle
What amino acid transfers Nitrogen to the liver for excretion?
Glutamine
What enzyme converts glutamate to glutamine?
Glutamate synthetase
- Adds another N from ammonia
What enzyme converts Glutamine to Glutamate through the removal of an N
Glutaminase
What does Glutamate Dehydrogenase convert Glutamate into?
- Removes another NH4+
a-ketoglutarate
Where is glutaminase found?
Liver
What alternate pathway is used by muscles to transfer nitrogen to the liver?
Alanine Cycle
What does ALT do in the Alanine cycle?
Passes NH2 from Glutamate to Pyruvate
- Creating Alanine
Also the reverse reaction
What is the structure of Alanine?
Pyruvate with an amino group
What is the purpose of alanine?
Can shuttle N to liver from muscle
a-ketoglutarate + NH2 will yield what amino acid?
- Catalyzed by ALT
Glutamate
What does Glutamate dehydrogenase in the liver do? (as part of the of alanine cycle)
Converts Glutamate into a-ketoglutarate and NH4+
What will mitochondrial disorders (e.g Pyruvate carboxylase and dehydrogenase deficiency) result in elevated levels of?
- Alanine
- Lactate
What is Urea synthesized from?
- NH4+
- CO2
- Aspartate
What enzyme is involved in the rate-limiting step of the urea cycle?
Carbamoyl Phosphate Synthetase I
Give the chemical equation for the rate limiting step of the urea cycle (Carbamoyl Phosphate Synthetase I)
NH4+ + CO2
-> Carbamoyl Phosphate
2 ATP -> 2ADP
What is the allosteric activator of Carbamoyl Phosphate Synthetase I?
N-acetylglutamate
- Used to regulate urea cycle
What is N-acetylglutamate (allosteric activator of Carbamoyl Phosphate Synthetase I) synthesized from?
- Glutamate
- Acetyl CoA
What is N-acetylglutamate (allosteric activator of Carbamoyl Phosphate Synthetase I) increased by?
Increased protein (fed state)
What is Carbamoyl Phosphate Synthetase II involved in?
Pyrimidine Synthesis
- Glutamate -> Carbamoyl Phosphate
What is the second reaction of the Urea cycle?
What enzyme creates Citrulline?
Ornithine Transcarbamylase
What is Citrulline created from?
Carbamoyl Phospahte + Ornithine
- Ornithine Transcarbamylase
The first 2 reactions of the Urea cycle occur where?
Mitochondria
Where is Ornithine created?
Cytosol
Where is Citrulline created? (and where does it go)
Mitochondria
- Goes to cytosol
What is Citrulline converted to in the Urea cycle?
Argininosuccinate (+ ATP + Aspartate)
What is Argininosuccinate converted into in the urea cycle?
Arginine (then converted to urea)
+ Fumarate
What makes Citrulline a non-standard amino acid?
- Not encoded by the genome
- Incorporated into proteins via post-translational modification
- More incorporation in inflammation
What are anti-citrulline antibodies found in?
Rheumatoid arthritis
Anti-Cyclic Citrullinated peptide antiBs (anti-CCP) are found in what patients?
Up to 80% of patients with RA
What molecule is depleted in hyperammonemia?
What other cycle does this disrupt
alpha-ketoglutarate (TCA cycle)
Hyperammonemia results in what in the CNS?
- Cerebral edema
- Tremor (asterixis)
- Memory impairment
- Slurred speech
- Vomiting
- Can progress to coma
How is hyperammonemia treated?
- Low protein diet
- Lactulose
How does lactulose treat hyperammonemia?
- Synthetic disaccharide (laxative)
- Colon breakdown by bacteria to fatty acids
- Lowers colonic pH; favors formation of NH4+ over NH3
- NH4+ not absorbed -> trapped in colon
- Decreasing ammonia plasma conc.
What treatments are used for hyperammonemia in enzyme deficiencies?
Ammonium detoxicants
- Na+ phenylbutyrate (oral)
- Na+ phenylacetate-Na+ benzoate (IV)
- Conjugate with glutamine
- Excreted in urine -> removal of nitrogen / ammonia
Arginine supplementation
- Urea cycle disorders make arginine essential
What is the most common urea cycle disorder?
OTC deficiency
How is OTC deficiency inherited?
X-linked recessive
What substances are increased in conc. in OTC deficiency?
- Carbamoyl phosphate
- Ammonia
- Orotic acid (derived from carbamoyl phosphate)
When do OTC deficiencies present?
Infancy or childhood (depending on severity)
What are common symptoms of OTC deficiency?
- Somnolence, poor feeding
- Seizures
- Vomiting
- Lethargy
- Coma
What can ditinguish OTC deficiency from orotic aciduria?
Only OTC has increased ammonia levels
What enzyme is deficient in orotic aciduria?
Uridine monophosphate synthase (UMPS)
What is citrullinemia a deficiency of (enzyme)?
Argininosuccinate synthase
What are the levels of different substances in citrullinemia?
- Elevated citrulline
- Low arginine
- Hyperammonemia
Urea cycle disorders generally present with what?
Hyperammonemia
- Build up of urea cycle intermediates
How are urea cycle disorders inherited?
Aut recessive
- Except OTC deficiency
