L19 - Ammonia Assimilation and Toxicity

Normal level of ammonia in the body; Too much ammonia causes what?

Between 10-30µM

Too much causes hyperammonemia:

80µM in infants up to 1 months

55µM in older children

30µM in adults

Hyperammonemia Causes

Urea cycle disorders are congenital conditions but depending on deficient enzyme, ammonia may build up and trigger due to stress/illness

Liver damage causes impairment to ammonia processing, occurs in severe liver diseases, and can also occur due to triggering events such as gastrointestinal bleeding or electrolyte imbalance.

Kidney failure

Blood disorders like myeloma or acute leukemia

Strong treatments such as chemotheraputics

Infection of urease-producing organisms

Hyperammonemia Treatments

Aromatic acid benzoate or phenylbutyrate can assimilate excess ammonia

Other therapies target specific enzyme deficiencies

Deficiencies in NAGS affects CPS-I, can be treated with carbonyl glutamate, a NAG analog that can activate CPS-I

Ornithine Transcarbamylase (OTC) Deficiency

Causes hyperammonemia and orotic aciduria

Type of UCD; CPS-I assimilates ammonia, but OTC enzyme is deficient and can’t catalyze the first reaction of Urea cycle, causing carbamoyl phosphate and ammonia buildup. This buildup causes leakage into the cytosol, where carbamoyl phosphate turns into orotic acid and causes orotic aciduria

Arginase Deficiency

Type of UCD: Causes episodic hyperammonemia, usually non-life-threatening

Individuals with this are typically fine at birth and early childhood, when excess arginine is needed anyway

Ammonia buildup isn’t as drastic here

Liver Acinus

Vascular system within the liver that helps to filter ammonia; Double-filtering system

Separated into zones:

• Zone 1: Portal vein, CPS-I and glutaminase is active here; low affinity, high capacity

• Zone 3: Glutamine synthetase is active here ; high affinity

Ammonia Assimilation

NOT transamination bc it does not decrease ammonia levels

Ammonia assimilation reactions are those that causes ammonia release/uptake

Glutamate dehydrogenase can both deaminate and assimilate ammonia; forward is called oxidative deamination and reverse is reductive amination

Glutamine synthetase: Uses E to form Q; assimilates; important in distant tissues

Glutamine synthetase

Catalyzes two-step reaction of NH₄⁺ with E to produce Q

Requires ATP; traps ammonia in the cytosol

Glutamine synthetase regulation

Allosterically inhibited by several end-products of glutamine

Importance of glutamine

Carries ammonia from muscles and brain to kidneys and liver

Very important in the brain

Essential for proteins and AA synthesis

Makes up 20% of total AA in body

Inter-organ nitrogen shuttle

Very important balance is needed. During hyperamonemia, glutamine formation may cause it to travel to the neuron, be processed back into ammonia, and cause problems.

Glutamate dehydrogenase and alanine aminotransferase can also help detoxify ammonia; Traps ammonia in the form of alanine.

Excitotoxicity

Occurs when excessive glutamates over stimulates neurons; leading to dysfunction; shows importance of glutamine synthetase

Disposition of AA carbon skeletons

Glycogenic/gluconeogenic AAs can be converted into intermediates in the TCA cycle and gluconeogenesis (A, D, N, E, & Q)

Ketogenic AAs can be converted to ketone bodies (K & L) (A, C, G, & S are potentially ketogenic)

AAs that are both keto and glycogenic: I, F, Y, W, T