Topics: Phenylketonuria, Tetrahydrobiopterin, Amino acid Pages: 4 (1272 words) Published: December 27, 2012
Phenylketonuria (PKU)
a) Discuss in molecular detail the genetic and biochemical basis for PKU. Phenylketonuria (an inborn error of metabolism) is characterized by mutations of the phenylalanine hydroxylase (PAH) gene. PAH converts phenylalanine (essential amino acid) into tyrosine and requires the cofactor tetrahydrobiopterin (BH4), molecular oxygen, and iron to do so. Loss of PAH activity results in increased concentrations of phenylalanine in the blood and toxic concentrations in the brain, causing mental retardation. During the hydroxylation of phenylalanine, by phenylalanine hydroxylase (PAH), and when molecular oxygen (O2) and iron (Fe2+) are present, tetrahydrobiopterin (BH4) is oxidized to a 4a-hydroxy-BH4 intermediate. This intermediate is subsequently regenerated back to BH4 via quinonoid (q) dihydrobiopterin, by the enzymes carbinolamie-4adehydratase (PCD), and by the NADH-dependent dihydropteridine reductase (DHPR). BH4 is synthesized from guanosine triphosphate (GTP) by three additional enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR). Mutations in genes coding for PCD, DHPR, GTPCH, PTPS, and SR result in BH4 deficiency. Therefore, hyperphenylalaninaemia is due to mutations in genes coding for enzymes involved in BH4 biosynthesis or regeneration. The PAH gene consists of 13 exons and their requisite introns. Phenylketonuria arises when both alleles are mutated. The two mutations can occur in any of the exons, in the splice junctions of the intervening introns, or perhaps in other as yet unidentified areas of the gene, such as in the promoter region. Phenylketonuria is inherited as an autosomal recessive condition. Those who have only one PAH mutation (eg, parents of a child with phenylketonuria) are carriers and have none of the biochemical or clinical characteristics of phenylketonuria. (1) b) Discuss methods currently used to treat PKU. What limitations and difficulties exist?...
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