Phenylalanine hydroxylase is an enzyme, which is necessary for the catalysis of phenylalanine to tyrosine. This catalysis is realized by hydroxylation of the aromatic side chain of phenylalanine. The enzyme needs tetrahydrobiopterin, BH4 a pteridine cofactor, and a non-heme iron for catalysis. In the reaction, molecular oxygen is cleaved. One oxygen atom is incorporated in BH4. The other oxygen atom is incorporated in phenylalanine. The reaction is shown in the following schema.
This reaction is the bottleneck in the metabolic pathway, which degrades phenylalanine. Mutations in the gene of PAH can cause the metabolomic disorder phenylketonuria. The structure of phenylalanine hydroxylase is very well reviewed. In this article we want to summarize the results in order to acquired more insight into the effect of mutations of the gene of phenylalanine hydroxylase.
In this illustration the binding pockets are very obvious. The red Fe atoms in the binding pockets mark their positions.
It is assumed, that the reaction takes place in three steps:
- formation of a Fe(II)-O-O-BH4 bridge
- heterolytic cleavage of the O-O bond to yield the ferryl oxo hydroxylating intermediate Fe(IV)=O
- attack on Fe(IV)=O to hydroxylate phenylalanine substrate to tyrosine.
Especially the formation of the Fe(II)-O-O-BH4 bridge is strongly discussed. Therefore most crystallographic experiments focus on the catalytic domain, which contains the BH4 and the Fe-atom.
Phenylalanine hydroxylase consists of three domains:
- a regulatory N-terminal domain (residues 1-117)
- the catalytic domain (residues 118-427)
- a C-terminal domain (residues 428-453) responsible for oligomerization of identical monomers
Phenylalanine hydroxylase has been the protein of the month (January 2005).