Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives
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...
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MDPI AG
2021-03-01
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| Series: | Biomolecules |
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| author | Raquel R. Lopes Catarina S. Tomé Roberto Russo Roberta Paterna João Leandro Nuno R. Candeias Lídia M. D. Gonçalves Miguel Teixeira Pedro M. F. Sousa Rita C. Guedes João B. Vicente Pedro M. P. Gois Paula Leandro |
| author_facet | Raquel R. Lopes Catarina S. Tomé Roberto Russo Roberta Paterna João Leandro Nuno R. Candeias Lídia M. D. Gonçalves Miguel Teixeira Pedro M. F. Sousa Rita C. Guedes João B. Vicente Pedro M. P. Gois Paula Leandro |
| author_sort | Raquel R. Lopes |
| collection | DOAJ |
| description | 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 <span style="font-variant: small-caps;">l</span>-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 <span style="font-variant: small-caps;">l</span>-Phe binding site, as supported by the solution structures obtained by small-angle X-ray scattering. |
| first_indexed | 2024-03-10T13:05:01Z |
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| id | doaj.art-930e60cb46ef4088b66394b0dbb9f7c4 |
| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-03-10T13:05:01Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-930e60cb46ef4088b66394b0dbb9f7c42023-11-21T11:12:03ZengMDPI AGBiomolecules2218-273X2021-03-0111346210.3390/biom11030462Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One DerivativesRaquel R. Lopes0Catarina S. Tomé1Roberto Russo2Roberta Paterna3João Leandro4Nuno R. Candeias5Lídia M. D. Gonçalves6Miguel Teixeira7Pedro M. F. Sousa8Rita C. Guedes9João B. Vicente10Pedro M. P. Gois11Paula Leandro12Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalFaculty of Engineering and Natural Sciences, Tampere University, Korkeakoulunkatu 8, 33101 Tampere, FinlandResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, PortugalInstituto de Biologia Experimental e Tecnológica, Quinta do Marquês, 2780-155 Oeiras, PortugalResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras, PortugalResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalPhenylketonuria (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 <span style="font-variant: small-caps;">l</span>-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 <span style="font-variant: small-caps;">l</span>-Phe binding site, as supported by the solution structures obtained by small-angle X-ray scattering.https://www.mdpi.com/2218-273X/11/3/462protein misfoldingdrug discoveryinherited metabolic disordersprotein drug interactionspharmacological chaperonesactivity chaperones |
| spellingShingle | Raquel R. Lopes Catarina S. Tomé Roberto Russo Roberta Paterna João Leandro Nuno R. Candeias Lídia M. D. Gonçalves Miguel Teixeira Pedro M. F. Sousa Rita C. Guedes João B. Vicente Pedro M. P. Gois Paula Leandro Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives Biomolecules protein misfolding drug discovery inherited metabolic disorders protein drug interactions pharmacological chaperones activity chaperones |
| title | Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
| title_full | Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
| title_fullStr | Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
| title_full_unstemmed | Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
| title_short | Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
| title_sort | modulation of human phenylalanine hydroxylase by 3 hydroxyquinolin 2 1h one derivatives |
| topic | protein misfolding drug discovery inherited metabolic disorders protein drug interactions pharmacological chaperones activity chaperones |
| url | https://www.mdpi.com/2218-273X/11/3/462 |
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