AA7 Ammonia Assimilation and toxicity

What are the normal blood ammonia levels by age?

• Infants: < 80 µM

• Older children: < 55 µM

  • Adults: < 30 µM

Why is ammonia toxic to cells?

It disrupts proton gradients, depletes α-ketoglutarate (α-KG) reducing TCA activity, and can cross the blood-brain barrier causing neurotoxicity.

What are common causes of hyperammonemia?

• Urea cycle enzyme deficiencies

• GI bleeding (increased protein turnover)

• Liver disease or acute liver failure

• Certain drugs or chemotherapy agents

• Severe muscle exertion

• Urease-producing bacterial infections

  • N-acetylglutamate synthase (NAGS) deficiency

What is used to treat NAGS deficiency?

Carbamyl glutamate, an analog of N-acetylglutamate that activates CPS1.

How does ammonia affect the brain?

Causes cognitive impairment, ataxia, seizures, and is highly neurotoxic due to interference with energy metabolism.

What percentage of ammonia in blood exists as the ammonium ion?

About 98%.

Name three key enzymes involved in ammonia assimilation.

• Glutamate dehydrogenase (GDH)

• Glutamine synthetase

  • Carbamoyl phosphate synthetase I (CPS1)

What is the reaction catalyzed by GDH during ammonia assimilation?

: α-ketoglutarate + NH₄⁺ + NADPH → Glutamate + NADP⁺ + H₂O

Where does GDH function occur?

In the mitochondria.

What reaction does glutamine synthetase catalyze?

Glutamate + NH₄⁺ + ATP → Glutamine + ADP + Pi

In which tissues is glutamine synthetase found?

Brain, liver, muscle, adipose tissue, and lungs.

Why is glutamine synthetase important?

It detoxifies ammonia, produces glutamine for nitrogen transport, and prevents neurotoxicity.

What regulates glutamine synthetase?

Feedback inhibition by alanine, glycine, and at least six other end products of glutamine metabolism.

How does glutamine synthetase respond to hyperammonemia?

It initially increases glutamine synthesis to buffer excess ammonia but can be inhibited if carbamoyl phosphate accumulates.

Why is glutamine important in the body?

• Major nitrogen carrier between tissues

• Most abundant amino acid in blood (~20% of total)

  • Used for protein synthesis, purine/pyrimidine synthesis, glucosamine, and carbamoyl phosphate formation.

What is the only enzyme that can synthesize glutamine de novo?

Glutamine synthetase.

Where is CPS1 located?

Mitochondria of liver cells.

What is a liver acinus?

The functional unit of the liver responsible for detoxifying blood as it flows from the portal vein to the central vein.

What are the two key zones of the liver acinus?

• Zone 1 (Periportal): High-capacity, low-affinity enzymes (urea cycle enzymes like CPS1).

  • Zone 3 (Perivenous): Low-capacity, high-affinity enzymes (glutamine synthetase).

What is the role of glutamine synthetase in the perivenous zone?

Removes any remaining ammonia by converting it to glutamine before blood exits the liver.

Which two major causes lead to hyperammonemia?

• Liver damage

  • Urea cycle disorders (genetic)

What is the most common inherited urea cycle disorder?

Ornithine transcarbamylase (OTC) deficiency.

What reaction is affected in OTC deficiency?

: Conversion of carbamoyl phosphate + ornithine → citrulline.

What accumulates as a result of OTC deficiency?

Carbamoyl phosphate.

What secondary condition can OTC deficiency cause?

Orotic aciduria (buildup of orotic acid in urine due to carbamoyl phosphate leaking into pyrimidine synthesis).

What are symptoms of OTC deficiency?

Hyperammonemia, lethargy, ataxia, and potentially death without intervention.

What is arginase deficiency?

A rare urea cycle disorder causing episodic hyperammonemia of varying severity.

When is arginase deficiency usually detected?

After birth or in early childhood; typically less severe than OTC deficiency.

What treatments can help with hyperammonemia?

• Sodium benzoate or sodium phenylbutyrate (bind nitrogen for excretion)

• Carbamyl glutamate for NAGS deficiency

• Limiting protein intake

• Supporting liver function