Dynamic regulation of phenylalanine hydroxylase

• Main Authors: Fuchs Julian E., Fuchs Dietmar, Liedl Klaus R.
• Format: Article
• Language: English
• Published: De Gruyter 2014-07-01
• Series: Pteridines
• Subjects: allostery; conformational dynamics; molecular dynamics simulation; phenylalanine hydroxylase; regulation.
• Online Access: https://doi.org/10.1515/pteridines-2014-0006
• ISSN: 0933-4807; 2195-4720

Phenylalanine hydroxylase (PAH) is the key enzyme in phenylalanine metabolism, catalyzing its oxidative breakdown to tyrosine. Its function in the committed step of amino acid metabolism requires strict regulation. Thus, several regulatory mechanisms are central for an understanding of PAH at the atomistic level. The enzyme is activated by incubation with phenylalanine and inhibited by tetrahydrobiopterin binding. Furthermore, phosphorylation of Ser-16 in the regulatory domain influences enzyme turnover. All major regulatory processes in PAH are connected to the conformational changes within a protein and its oligomeric assembly. The underlying dynamic processes in the enzyme are tackled by a variety of experimental and computational approaches. We especially emphasize the computational approaches, aiming to unravel the changes in the molecular dynamics of PAH that govern allosteric regulation. State-of-the-art molecular dynamics simulations provide access to the conformational transitions in biological macromolecules at the microsecond time scale and beyond. Thus, in silico strategies are promising for the identification of the complex allosteric mechanisms governing PAH activity in vivo.