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Open AccessArticle

Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives

1
Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
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Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, Portugal
3
Instituto de Biologia Experimental e Tecnológica, Quinta do Marquês, 2780-155 Oeiras, Portugal
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Faculty of Engineering and Natural Sciences, Tampere University, Korkeakoulunkatu 8, 33101 Tampere, Finland
5
LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
*
Authors to whom correspondence should be addressed.
Current address: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Academic Editors: Supriyo Bhattacharya and Vladimir N. Uversky
Biomolecules 2021, 11(3), 462; https://doi.org/10.3390/biom11030462
Received: 6 January 2021 / Revised: 8 February 2021 / Accepted: 13 March 2021 / Published: 19 March 2021
(This article belongs to the Section Natural and Bio-inspired Molecules)
Phenylketonuria (PKU) is a genetic disease caused by deficient activity of human phenylalanine 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. View Full-Text
Keywords: protein misfolding; drug discovery; inherited metabolic disorders; protein drug interactions; pharmacological chaperones; activity chaperones protein misfolding; drug discovery; inherited metabolic disorders; protein drug interactions; pharmacological chaperones; activity chaperones
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MDPI and ACS Style

Lopes, R.R.; Tomé, C.S.; Russo, R.; Paterna, R.; Leandro, J.; Candeias, N.R.; Gonçalves, L.M.D.; Teixeira, M.; Sousa, P.M.F.; Guedes, R.C.; Vicente, J.B.; Gois, P.M.P.; Leandro, P. Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives. Biomolecules 2021, 11, 462. https://doi.org/10.3390/biom11030462

AMA Style

Lopes RR, Tomé CS, Russo R, Paterna R, Leandro J, Candeias NR, Gonçalves LMD, Teixeira M, Sousa PMF, Guedes RC, Vicente JB, Gois PMP, Leandro P. Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives. Biomolecules. 2021; 11(3):462. https://doi.org/10.3390/biom11030462

Chicago/Turabian Style

Lopes, Raquel R.; 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. 2021. "Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives" Biomolecules 11, no. 3: 462. https://doi.org/10.3390/biom11030462

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