Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/59289 |
Resumo: | 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. |
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Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivativesprotein misfoldingdrug discoveryinherited metabolic disordersprotein drug interactionspharmacological chaperonesactivity chaperonesPhenylketonuria (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.This work was supported by FEDER and Fundação para a Ciência e a Tecnologia, I. P. through national funds (Projects UIDB/04138/2020 and UIDP/04138/2020 and research project PTDC/MED-QUI/29712/2017). This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie-Sklodowska Curie grant agreement No [675007], LISBOA-01-0145-FEDER-029967 and PTDC/QUI-QOR/29967/2017. Principal Researcher grant CEECIND/03143/2017 (Fundação para a Ciência e a Tecnologia) is acknowledged by L.M.D.G. European Union’s Horizon 2020 research and innovation programme (grant agreement No 810856) is acknowledged by M.T. iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged by J.B.V.MDPIRepositório da Universidade de LisboaLopes, Raquel R.Tomé, Catarina S.Russo, RobertoPaterna, RobertaLeandro, JoãoCandeias, Nuno R.Gonçalves, LídiaTeixeira, MiguelSousa, Pedro M. F.Guedes, R. C.Vicente, João B.Gois, Pedro M. P.Leandro, Paula2023-09-14T11:41:24Z2021-03-192023-02-27T15:45:20Z2021-03-19T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/59289engLopes RR, Tomé CS, Russo R, Paterna R, Leandro J, Candeias NR, et al. Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives. Biomolecules [Internet]. 2021 Mar 19;11(3):462. Available from: http://dx.doi.org/10.3390/biom110304622218-273Xcv-prod-277925110.3390/biom11030462info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T17:04:04Zoai:repositorio.ul.pt:10451/59289Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:07:00.088260Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
title |
Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
spellingShingle |
Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives Lopes, Raquel R. protein misfolding drug discovery inherited metabolic disorders protein drug interactions pharmacological chaperones activity chaperones |
title_short |
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_sort |
Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives |
author |
Lopes, Raquel R. |
author_facet |
Lopes, Raquel R. Tomé, Catarina S. Russo, Roberto Paterna, Roberta Leandro, João Candeias, Nuno R. Gonçalves, Lídia Teixeira, Miguel Sousa, Pedro M. F. Guedes, R. C. Vicente, João B. Gois, Pedro M. P. Leandro, Paula |
author_role |
author |
author2 |
Tomé, Catarina S. Russo, Roberto Paterna, Roberta Leandro, João Candeias, Nuno R. Gonçalves, Lídia Teixeira, Miguel Sousa, Pedro M. F. Guedes, R. C. Vicente, João B. Gois, Pedro M. P. Leandro, Paula |
author2_role |
author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Lopes, Raquel R. Tomé, Catarina S. Russo, Roberto Paterna, Roberta Leandro, João Candeias, Nuno R. Gonçalves, Lídia Teixeira, Miguel Sousa, Pedro M. F. Guedes, R. C. Vicente, João B. Gois, Pedro M. P. Leandro, Paula |
dc.subject.por.fl_str_mv |
protein misfolding drug discovery inherited metabolic disorders protein drug interactions pharmacological chaperones activity chaperones |
topic |
protein misfolding drug discovery inherited metabolic disorders protein drug interactions pharmacological chaperones activity chaperones |
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 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. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-03-19 2021-03-19T00:00:00Z 2023-09-14T11:41:24Z 2023-02-27T15:45:20Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/59289 |
url |
http://hdl.handle.net/10451/59289 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Lopes RR, Tomé CS, Russo R, Paterna R, Leandro J, Candeias NR, et al. Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives. Biomolecules [Internet]. 2021 Mar 19;11(3):462. Available from: http://dx.doi.org/10.3390/biom11030462 2218-273X cv-prod-2779251 10.3390/biom11030462 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
dc.publisher.none.fl_str_mv |
MDPI |
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MDPI |
dc.source.none.fl_str_mv |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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