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

Detalhes bibliográficos
Autor(a) principal: Lopes, Raquel R.
Data de Publicação: 2021
Outros Autores: 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
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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spelling 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
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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