Modulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivatives
| Autor(a) principal: | |
|---|---|
| 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/10362/120790 |
Resumo: | Funding Information: We are grateful to Cristina Leit?o (ITQB-NOVA) for expert technical assistance on the HPLC assays. We thank the Diamond Light Source for access to beamline B21 (proposal mx20161) and the technical support from Katsuaki Inoue, that contributed to the results presented here.This work was supported by FEDER and Funda??o para a Ci?ncia 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 (Funda??o para a Ci?ncia 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 Funda??o para a Ci?ncia e a Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged by J.B.V. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved. |
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Modulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivativesActivity chaperonesDrug discoveryInherited metabolic disordersPharmacological chaperonesProtein drug interactionsProtein misfoldingBiochemistryMolecular BiologySDG 3 - Good Health and Well-beingFunding Information: We are grateful to Cristina Leit?o (ITQB-NOVA) for expert technical assistance on the HPLC assays. We thank the Diamond Light Source for access to beamline B21 (proposal mx20161) and the technical support from Katsuaki Inoue, that contributed to the results presented here.This work was supported by FEDER and Funda??o para a Ci?ncia 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 (Funda??o para a Ci?ncia 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 Funda??o para a Ci?ncia e a Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged by J.B.V. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.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.Instituto de Tecnologia Química e Biológica António Xavier (ITQB)RUNLopes, Raquel R.Tomé, Catarina S.Russo, RobertoPaterna, RobertaLeandro, JoãoCandeias, Nuno R.Gonçalves, Lídia M.D.Teixeira, MiguelSousa, Pedro M.F.Guedes, Rita C.Vicente, João B.Gois, Pedro M.P.Leandro, Paula2021-07-09T22:18:00Z2021-032021-03-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article25application/pdfhttp://hdl.handle.net/10362/120790eng2218-273XPURE: 32441039https://doi.org/10.3390/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:RCAAP2024-05-22T17:54:32Zoai:run.unl.pt:10362/120790Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-05-22T17:54:32Repositório 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. Activity chaperones Drug discovery Inherited metabolic disorders Pharmacological chaperones Protein drug interactions Protein misfolding Biochemistry Molecular Biology SDG 3 - Good Health and Well-being |
| 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 M.D. Teixeira, Miguel Sousa, Pedro M.F. Guedes, Rita 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 M.D. Teixeira, Miguel Sousa, Pedro M.F. Guedes, Rita 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 |
Instituto de Tecnologia Química e Biológica António Xavier (ITQB) RUN |
| dc.contributor.author.fl_str_mv |
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 |
| dc.subject.por.fl_str_mv |
Activity chaperones Drug discovery Inherited metabolic disorders Pharmacological chaperones Protein drug interactions Protein misfolding Biochemistry Molecular Biology SDG 3 - Good Health and Well-being |
| topic |
Activity chaperones Drug discovery Inherited metabolic disorders Pharmacological chaperones Protein drug interactions Protein misfolding Biochemistry Molecular Biology SDG 3 - Good Health and Well-being |
| description |
Funding Information: We are grateful to Cristina Leit?o (ITQB-NOVA) for expert technical assistance on the HPLC assays. We thank the Diamond Light Source for access to beamline B21 (proposal mx20161) and the technical support from Katsuaki Inoue, that contributed to the results presented here.This work was supported by FEDER and Funda??o para a Ci?ncia 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 (Funda??o para a Ci?ncia 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 Funda??o para a Ci?ncia e a Tecnologia/Minist?rio da Ci?ncia, Tecnologia e Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged by J.B.V. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2021 Elsevier B.V., All rights reserved. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021-07-09T22:18:00Z 2021-03 2021-03-01T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10362/120790 |
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http://hdl.handle.net/10362/120790 |
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eng |
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eng |
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2218-273X PURE: 32441039 https://doi.org/10.3390/biom11030462 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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25 application/pdf |
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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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mluisa.alvim@gmail.com |
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