Phenylketonuria is an autosomal recessive disorder and a common metabolic cause of mental retardation. This inborn error of metabolism is characterized by a deficiency in phenylalanine (Phe) hydroxylase activity, due to mutations in the Phe hydroxylase (PAH) gene. Phenylalanine hydroxylase is responsible for converting Phe to Tyr and requires the cofactor tetrahydrobiopterin (BH4), molecular oxygen, and iron for its action (Blau et al., 2010). The reductant, BH4 is maintained in the reduced state by the NADH-dependent enzyme dihydropteridine reductase. Decreased PAH activity results in elevated Phe concentrations in blood and body tissue. As a result, approximately 75% of untreated patients experience severe neurological dysfunction (Brumm and Grant, 2010).
Phe is a large neutral amino acid that competes for transport across the blood brain barrier via the L-type amino acid carrier. Excessive levels of Phe in the blood saturates these transporters and subsequently cause a decrease in transportation of other large neutral amino acids into the brain which is required for protein and neurotransmitter synthesis (Blau et al., 2010). Neurological …show more content…
Defects in the synthesis or recycling of BH4 could lead to phenotypical characteristics of phenylketonuria. During the hydroxylation of Phe by PAH in the presence of molecular oxygen and iron, BH4 is oxidized to a 4a-hydroxy-BH4 intermediate, which in turn is converted to q-dihydrobiopterin by cabinolamine-4a-dehydratase (Blau et al., 2010). Which is subsequently regenerated back to BH4 by the NADH dependent enzyme, dihydropteridine reductase. Mutations in any of the genes coding for the above mentioned enzymes involved, result in decreased BH4 levels and consequently phenylketonuria due to the elevated plasma Phe
Phe is a large neutral amino acid that competes for transport across the blood brain barrier via the L-type amino acid carrier. Excessive levels of Phe in the blood saturates these transporters and subsequently cause a decrease in transportation of other large neutral amino acids into the brain which is required for protein and neurotransmitter synthesis (Blau et al., 2010). Neurological …show more content…
Defects in the synthesis or recycling of BH4 could lead to phenotypical characteristics of phenylketonuria. During the hydroxylation of Phe by PAH in the presence of molecular oxygen and iron, BH4 is oxidized to a 4a-hydroxy-BH4 intermediate, which in turn is converted to q-dihydrobiopterin by cabinolamine-4a-dehydratase (Blau et al., 2010). Which is subsequently regenerated back to BH4 by the NADH dependent enzyme, dihydropteridine reductase. Mutations in any of the genes coding for the above mentioned enzymes involved, result in decreased BH4 levels and consequently phenylketonuria due to the elevated plasma Phe