Evolution of regulation, structure and function in phenylalanine hydroxylase
Conference
Siltberg-Liberles, J, Flydal, MI, Teigen, K et al. (2009). Evolution of regulation, structure and function in phenylalanine hydroxylase
. 20(SPECIAL ISSUE), 42-50.
Siltberg-Liberles, J, Flydal, MI, Teigen, K et al. (2009). Evolution of regulation, structure and function in phenylalanine hydroxylase
. 20(SPECIAL ISSUE), 42-50.
Phenylalanine hydroxylase (PAH) catalyzes the para-hydroxylation of L-Phe to L-Tyr, which in mammals is the first step in the catabolic degradation of L-Phe. Defects in PAH, notably due to mutations in the PAH gene, result in high concentrations of L-Phe in plasma, causing phenylketonuria (PKU) in humans. In order to maintain L-Phe homeostasis, PAH has thus developed increasingly sophisticated regulatory mechanisms during evolution. In mammals PAH is subjected to strict control, mainly by its substrate L-Phe, via activation and positive cooperativity and inhibition by the cofactor tetrahydrobiopterin. On the other hand, PAHs from bacteria and lower eukaryotes, which have been associated to the synthesis of L-Tyr derivatives such as melanine-like compounds, do not show allosteric regulation. We have analyzed the sequence and structure of PAH from an evolutionary perspective in an effort to explain the structural determinants for the incorporation of regulatory properties in mammals. Sites with a high probability of being involved in a functional or regulatory change were identified using Diverge. The structures of PAH from human, and Caenorhabditis elegans were modeled and used to visualize the changed sites. Important areas with high probability of being involved in allosteric regulation of mammalian PAH are discussed.
