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Modulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivatives

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Resumo:Phenylketonuria (PKU) is a genetic disease caused by deficient activity of human pheny-lalanine hydroxylase (hPAH) that, when untreated, can lead to severe psychomotor impairment. Protein misfolding is recognized as the main underlying pathogenic mechanism of PKU. Therefore, the use of stabilizers of protein structure and/or activity is an attractive therapeutic strategy for this condition. Here, we report that 3-hydroxyquinolin-2(1H)-one derivatives can act as protectors of hPAH enzyme activity. Electron paramagnetic resonance spectroscopy demonstrated that the 3-hydroxyquinolin-2(1H)-one compounds affect the coordination of the non-heme ferric center at the enzyme active-site. Moreover, surface plasmon resonance studies showed that these stabilizing compounds can be outcompeted by the natural substrate L-phenylalanine. Two of the designed compounds functionally stabilized hPAH by maintaining protein activity. This effect was observed on the recombinant purified protein and in a cellular model. Besides interacting with the catalytic iron, one of the compounds also binds to the N-terminal regulatory domain, although to a different location from the allosteric L-Phe binding site, as supported by the solution structures obtained by small-angle X-ray scattering.
Autores principais:Lopes, Raquel R.
Outros Autores:Tomé, Catarina S.; Russo, Roberto; Paterna, Roberta; Leandro, João; Candeias, Nuno R.; Gonçalves, Lídia M.D.; Teixeira, Miguel; Sousa, Pedro M.F.; Guedes, Rita C.; Vicente, João B.; Gois, Pedro M.P.; Leandro, Paula
Assunto:Activity chaperones Drug discovery Inherited metabolic disorders Pharmacological chaperones Protein drug interactions Protein misfolding Biochemistry Molecular Biology SDG 3 - Good Health and Well-being
Ano:2021
País:Portugal
Tipo de documento:artigo
Tipo de acesso:acesso aberto
Instituição associada:Universidade Nova de Lisboa
Idioma:inglês
Origem:Repositório Institucional da UNL

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