Basic Research on Phenylketonuria (PKU)

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Phenylketonuria (PKU)

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Testing for PAH Mutations

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hTrpOH

hPehOH

rTyrOH

Mutations in the gene encoding for PheOH is responsible for the metabolic disorder phenylketonuria (PKU), or the milder form hyperphenylalaninemia (HPA). These mutations of PheOH disrupt either its catalytic function or reduces the stability of the enzyme, thus resulting in increased levels of non-catabolized phenylalanine in the blood stream. This again results in phenylalanine being converted into phenylketones (like phenylpyruvate) instead, which together with phenylalanine on it's own is neurotoxic, and cause mental retardation in humans suffering from PKU. Currently there are over 400 mutations known to cause either severe PKU or HPA.

The mutations are continuously being catalogued in a curated database with a molecular modelling site

Analysis of the protein structure of human PheOH reveals that the PKU mutations occur over all regions of the protein structure, and a mapping of the single point mutations onto the crystal structure of PheOH shows that most of them are accumulated in the catalytic domain (coloured red, blue, magenta and green; yellow means no mutation) and a few in the regulatory domain.

Above are two illustations showing (A) the overall structure of the full-length monomer model based on the crystals structures of various truncations of PheOH, and (B) the model of the full-length tetramer.

In addition to phenylalanine hydroxylase (PheOH) Our lab has been interested in the structural basis of neurotransmitter biosynthesis since the start and have succeeded in determining the three-dimensional structure of tyrosine hydroxylase (TyrOH) and tryptophan hydroxylase (TrpOH).

Phenylalanine hydroxylase (PheOH) converts the essential amino acid L-Phenylalanine (L-Phe) into L-Tyrosine (L-Tyr). This is the major route for catabolization of dietary L-Phe. PheOH utilizes the cofactor 5,6,7,8-tetrahydrobiopterin (BH4) along with molecular oxygen to convert L-Phe to L-Tyr and is a member of the small sub-family of enzymes denoted the aromatic amino acid hydroxylases, along with tyrosine hydroxylase (TyrOH) and tryptophan hydroxylase (TrpOH).


The biosynthesis of the neurotransmitters dopamine, adrenaline, and noradrenaline from dietary phenylalanine (into tyrosine) is inititated by the enzyme phenylalanine hydroxylase. Tyrosine is then converted to L-DOPA (3,4-dihydroxyphenylalanine) next, in the rate-limiting step of neurotransmitter biosynthesis. This reaction is catalyzed by the homologous enzyme tyrosine hydroxylase, which utilizes tetrahydrobiopterin and molecular oxygen as cofactors in the hydroxylation reaction ina manner similar to the reaction of phenylalanine hydroxylase. Together with tryptophan hydroxylase, these two enzymes constitute the small superfamily of the aromativ amino acid hydroxylases. The conversion of L-DOPA into dopamine is catalyzed by DOPA decarboxylase (aromatic L-amino acid decarboxylase) and subsequently into noradrenaline by dopamine beta-hydroxylase and adrenaline by noradrenaline N-methyltransferase (Phenylethanolamine N-methyltransferase).