15. Enzymopathies of amino acid metabolism

Last updated on July 3, 2020 at 10:43

Learning objectives

  • Why is ammonia toxic to the brain?
  • Which enzyme is defect in the diseases mentioned?

Hyperammonaemia

As outlined before, too much ammonia is very bad. It can easily cross the blood-brain barrier, so it is toxic to the brain. If the brain contains too much ammonia, it will try to get rid of it in two ways.

The first is by the glutamate dehydrogenase reaction, which converts α-ketoglutarate and ammonium to glutamate. However, this depletes α-ketoglutarate, which is essential for the TCA.

The second is by converting glutamate and ammonium to glutamine in the glutaminase reaction. However, this will deplete glutamate, which is the direct precursor to GABA, an important neurotransmitter.

Hyperammonaemia is a result of either urea cycle defects, as the body has trouble excreting ammonia, or by permanent activation of glutamate dehydrogenase, which breaks down glutamate into α-ketoglutarate and ammonia.

Urea cycle enzyme defects

Defective enzyme Disease
Carbamoyl phosphate synthetase I (CPS I) Congenital hyperammonemia type I
Ornithine transcarbamoylase Congenital hyperammonemia type II
Argininosuccinate synthetase Citrullinemia
Argininosuccinase Argininosuccinate aciduria
Arginase Argininemia (arginase deficiency)
N-acetylglutamate synthase N-acetylglutamate synthase deficiency

Genetic disorders of amino acid degradation

Affected enzyme Affected pathway Disease
Glycine cleavage enzyme Glycine degradation Hyperglycinaemia
Branched-chain α-keto acid dehydrogenase complex Branched chain amino acid degradation Maple syrup urine disease
Methylmalonyl-CoA mutase Valine, isoleucine, threonine, methionine degradation Methylmalonic acidaemia
Cystathionine β-synthase Methionine degradation Homocysteinuria I
Phenylalanine hydroxylase Phenylalanine degradation Phenylketonuria
Tyrosine aminotransferase Phenylalanine degradation Tyrosinaemia II
p-hydroxyphenylpyruvate dioxygenase Phenylalanine degradation Tyrosinaemia III
Homogentisate 1,2-dioxygenase Phenylalanine degradation Alkaptonuria
Fumarylacetoacetase Phenylalanine degradation Tyrosinaemia I
Tyrosinase Melanin synthesis from tyrosine Albinism

Methylmalonic acidaemia/aciduria

In 1991 a woman called Patricia Stallings was convicted of the murder of her own son Ryan, after tests seemed to point to elevated levels of ethylene glycol (antifreeze) in her son’s blood. She was convicted of poisoning her own son with antifreeze in 1989. In 1990 she gave birth to a second son, who soon became sick but was diagnosed with methylmalonic acidaemia before serious damage occurred.

This made it likely that Ryan also had methylmalonic acidaemia, but this disease doesn’t cause accumulation of ethylene glycol, so no connection between the two were made. After a biochemist watched an episode on Unresolved Mysteries regarding the occurrence it was eventually discovered that the test method used to test for ethylene glycol in blood would be positive in cases of methylmalonic acidaemia, as this disease causes accumulation of propionic acid, a similar molecule. This proved that Ryan also died from methylmalonic acidaemia and not from poisoning. Stallings was released from prison and sued the hospital and laboratories involved.

Phenylketonuria

Phenylketonuria is a genetic disease caused by deficiency of phenylalanine hydroxylase, an enzyme involved in the conversion of phenylalanine to tyrosine. This causes phenylalanine to be degraded by an alternative pathway which converts phenylalanine into other metabolites instead.

Accumulation of phenylalanine is harmful to the brain, but harmful effects occur also from the tyrosine deficiency. In these people tyrosine becomes an essential amino acid. This is a problem as tyrosine is a precursor for neurotransmitters, melanin, and thyroid hormones.

Maple syrup urine disease

Maple syrup urine disease is a genetic disease caused by deficiency of branched-chain α-keto acid dehydrogenase complex. This disease leads to accumulation of the branched-chain amino acids as well as their keto-acid metabolites. It causes a characteristic sweet-smelling urine, hence the name.

Summary

  • Why is ammonia toxic to the brain?
    • The brain removes ammonia in two ways
    • The first is by the glutamate dehydrogenase reaction, which converts α-ketoglutarate and ammonium to glutamate. However, this depletes α-ketoglutarate, which is essential for the TCA.
    • The second is by converting glutamate and ammonium to glutamine in the glutaminase reaction. However, this will deplete glutamate, which is the direct precursor to GABA, an important neurotransmitter.
  • Which enzyme is defect in the diseases mentioned?
    • See here for a summary of all diseases you must know

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14. Synthesis of non-essential amino acids

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16. Synthesis of biologically active molecules from amino acids

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