Metabolic Case II: Hyperammonemia Flashcards
(35 cards)
What does OTC stand for? What is the starting substrate and end product for the OTC reaction?
Ornithine Transcarbamoylase
- Carbamoyl phosphate > Citrulline
What is an OTC Deficiency and what does it result in (2)?
OTC Deficiency is the inability to synthesize citrulline and because all subsequent reactions rely on citrulline, urea synthesis is decreased and the Urea Cycle is slowed
What is Hyperammonemia? What are the two types of Hyperammonemia?
Hyperammonemia is the accumulation of NH4+ in the cytoplasm of liver cells, which eventually diffuses into the blood as NH3
- Hereditary hyperammonemia
- Acquired hyperammonemia
Compare the causes of Hereditary hyperammonemia versus Acquired hyperammonemia in OTC deficiency
- Hereditary hyperammonemia: caused by a genetic defect in any one of the 5 enzymes or 2 transporters in the Urea Cycle
- Acquired hyperammonemia: caused by liver cirrhosis
Explain the mechanism behind Acquired hyperammonemia in OTC deficiency
When liver cells are damaged by liver cirrhosis, they are replaced by fibroblast cells, but these fibroblast cells do not have the enzyme necessary to break down NH4+ and it instead accumulates
- The NH4+ is diverted into the systemic circulation
What molecule is increased with hyperammonemia, and why?
Glutamine levels are increased with hyperammonemia
- Urea Cycle is compromised so the Glutamine Synthetase reaction occurs to try to mop-up the excess NH4+ in the cells (NH4+ > Glutamine)
Why is there still excess NH4+ in the blood even though the Glutamine Synthetase reaction is taking place with an OTC deficiency?
The Glutamine Synthetase reaction has a low capacity so while it can mop up some of the NH4+ in the cells, it becomes overwhelmed and cannot get it all - ultimately some of the NH3 in the blood will continue on as NH4+
What are the two primary causes of neurological toxicity in the cell cytoplasm with an OTC deficiency?
- Increased NH4+
- Increased Glutamine (from Glutamine Synthetase reaction)
What type of brain cell is most affected by increased NH4+ and increased glutamine/glutamate levels?
Astrocytes (neuronal cells)
- Swell up and become damaged (from high glutamine levels)
- Cell death (from high glutamate levels)
How do increased NH4+ and increased glutamine levels cause neurological toxicity with an OTC deficiency? How does this present symptomatically?
Glutamine is osmotically active so it pulls water into astrocytes causing swelling and damage
- Leads to cerebral edema, altered neural signaling and coma in brain cells
What are the two primary causes of neuronal cell death with an OTC deficiency?
- Increased NH4+
- Increased Glutamate (from Glutamate Dehydrogenase)
How do increased NH4+ and increased glutamate levels cause astrocyte cell death with an OTC deficiency?
The damaged astrocytes from high glutamine levels cannot take up the excess synaptic glutamate, resulting in death of the damaged astrocytes
What are CPSI and CPSII? Where in the cell are they located and for which reactions are they used?
- CPSI: found in mitochondria and used in Urea Cycle
- CPSII: found in cytoplasm and used in UMP nucleotide synthesis pathway
What is an important intermediate of the UMP nucleotide synthesis pathway, and if it is elevated, what problem does it indicate in the presence of hyperammonemia?
Orotic acid is an intermediate of the UMP nucleotide synthesis pathway
- When orotic acid levels are elevated, it indicates that hyperammonemia is due to an OTC defect
How do high levels orotic acid indicate that hyperammonemia is due to an OTC deficiency?
When carbamoyl phosphate(mito) builds up from an OTC deficiency, it leaks into the cytoplasm where it becomes carbamoyl phosphate(cyto)
- In the cytoplasm, carbamoyl phosphate produces orotic acid as an intermediate of the UMP nucleotide synthesis pathway
What are the two primary treatments for an OTC deficiency, and why?
- Low-protein diet: reduces dietary AAs consumed > reduce N from those AAs
- Citrulline supplements: Urea Cycle will be restored
Explain how Citrulline supplements restore the Urea Cycle for an OTC deficiency
If Citrulline supplements (1 N) are introduced, the Citrulline will combine with Aspartate (1 N) to produce Urea (2 N), which can then be excreted from the body
How does use of Citrulline supplements differ from the normal Urea Cycle?
The Citrulline supplement already has a N attached to it, so only 1 body N is excreted from the body rather than the 2 N that would normally be excreted with the Urea Cycle (slower with supplements, but better than nothing)
What are the recommended ACUTE and CHRONIC treatments for Hereditary hyperammonemia? What is found in these solutions and how are they administered?
- Acute: Ammonul (Sodium Benzoate and Sodium Phenylbutyrate, given IV)
- Chronic: Buphenyl (only Sodium Phenylbutyrate, given orally)
What are the starting substrates and end products for Sodium Benzoate? Where are the N found in this reaction?
Benzoate + Glycine (1 N) > Hippurate (1 N)
What are the starting substrates and end products for Sodium Phenylbutyrate? Where are the N found in this reaction?
Phenylbutyrate > Phenylacetate + Glutamine (2 N) > Phenylacetylglutamine (2 N)
What are the products of the Sodium Benzoate and Sodium Phenylbutyrate reactions and what happens to these products?
Hippurate and Phenylacetylglutamine are safely excreted in the urine without use of the Urea Cycle
What is the rate limiting enzyme of beta-oxidation and what is its function?
CPTI is the rate limiting enzyme of beta-oxidation and it transports Fatty Acyl CoA from the cytoplasm to the mitochondria
What are the normal starting substrates and end products of beta-oxidation? What is an indirect product of beta-oxidation?
FAs > Acetyl CoA + NADH + FADH2
- Indirectly produces lots of ATP via the ETC
