Sandbox Reserved 1734: Difference between revisions

L-Tyrosine is the precursor to neurotransmitters such as epinephrine, dopamine, and serotonin (8). It is essential that L-phenylalanine is converted into L-tyrosine by the hydroxylation reaction. In order for this conversion to be successful, the enzyme phenylalanine hydroxylase needs to be able to function properly. PAH depletion or <scene name='91/919043/Mutation/1'>mutation</scene> leads to excessive accumulation of toxic L-Phe levels. However, normal physiological plasmatic levels of L-phenylalanine are less than 120 micromolar (4). Not only does dysfunctional PAH lead to increased phenylalanine levels in the blood, but it also has the appearance of urine metabolites that arise from the transamination of L-Phe to phenylpyruvate (4). When the enzyme PAH doesn’t function correctly, the autosomal recessive metabolic disorder Phenylketonuria (PKU) occurs. PKU is a congenital disorder characterized by excessive amounts of L-phenylalanine that buildup to neurotoxic amounts leading to cognitive disability and neurological impairment, including profound mental retardation, seizures, microcephaly, and delayed development (2, 3, & 6). The severity of PKU is dependent upon the severity of the enzyme’s mutation (3 & 10). PAH mutations result in reduced enzyme activity and stability and some alter their oligomeric state (6). These mutations spread throughout the 3D structure, but most are located in the catalytic domain (10). Loss of enzymatic function is caused mainly by folding defects that lead to decreased protein stability (6). The mutation leads to a truncated form of the final 52 amino acids. These C-terminal amino acids are a part of the tetramerization domain. Another frequent mutation is a CGG-to-TGG transition on exon 12. This mutation leads to a substitution of Arginine for Tryptophan at position 408. This missense mutation results in undetectable levels of phenylalanine and the severe PKU phenotype (10).

Treatments for phenylketonuria include a lifelong diet avoiding foods containing phenylalanine and supplementation of synthetic formations of the cofactor tetrahydrobiopterin (BH4) (11). Testing for PKU can be done early on in the lifespan to determine if the disease is present and to start avoiding foods containing phenylalanine (3).