Pharmacological Chaperones that Protect Tetrahydrobiopterin Dependent Aromatic Amino Acid Hydroxylases Through Different Mechanisms

The aromatic amino acid hydroxylase (AAAH) enzyme family includes phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH) and the tryptophan hydroxylases (TPH1 and TPH2). All four members of the AAAH family require iron, dioxygen and the cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) to hydroxylate their respective substrates. The AAAHs are involved in severe diseases; whereas polymorphisms and variants in the TPH genes are associated to neuropsychiatric disorders, mutations in PAH and TH are responsible for the autosomal recessive disorders phenylketonuria (PKU) and TH deficiency (THD), respectively. A large number of PKU and THD-causing mutations give rise to unstable, misfolded proteins. The degree of conformational instability correlates well with the severity of the patient phenotypes, underlying the relevance of searching for stabilizing compounds that may protect from loss of protein and activity in vivo. Supplementation with the cofactor BH4 exerts a multifactorial response in PAH, where one of the main mechanisms for the induced increase in PAH activity in BH4- responsive PKU patients appears to be a pharmacological chaperone effect. For TH the stabilizing effect of BH4 is less established. On the other hand, a number of compounds with pharmacological chaperone potential for PKU and THD mutants have been discovered. The stabilizing effect of these compounds has been established in vitro, in cells and in animal models. A recent study with TH has revealed different mechanisms for the action of pharmacological chaperones and identifies a subtype of compounds that preserve TH activity by weak binding to the catalytic iron. It is expected that synergistic combinations of different pharmacological chaperones could provide patient-tailored therapeutic options.

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