Publicação
Modulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivatives
| Resumo: | 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. |
|---|---|
| Autores principais: | Lopes, Raquel R. |
| Outros Autores: | 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 |
| Assunto: | Activity chaperones Drug discovery Inherited metabolic disorders Pharmacological chaperones Protein drug interactions Protein misfolding Biochemistry Molecular Biology SDG 3 - Good Health and Well-being |
| Ano: | 2021 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| _version_ | 1868415369990897664 |
|---|---|
| author | Lopes, Raquel R. |
| 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 |
| 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 |
| contributor_name_str_mv | Instituto de Tecnologia Química e Biológica António Xavier (ITQB) MDPI - Multidisciplinary Digital Publishing Institute RUN |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Lopes, Raquel R.\"},{\"Person.name\":\"Tomé, Catarina S.\"},{\"Person.name\":\"Russo, Roberto\"},{\"Person.name\":\"Paterna, Roberta\"},{\"Person.name\":\"Leandro, João\"},{\"Person.name\":\"Candeias, Nuno R.\"},{\"Person.name\":\"Gonçalves, Lídia M.D.\"},{\"Person.name\":\"Teixeira, Miguel\"},{\"Person.name\":\"Sousa, Pedro M.F.\"},{\"Person.name\":\"Guedes, Rita C.\"},{\"Person.name\":\"Vicente, João B.\"},{\"Person.name\":\"Gois, Pedro M.P.\"},{\"Person.name\":\"Leandro, Paula\"}] |
| datacite.contributors.contributor.contributorName.fl_str_mv | Instituto de Tecnologia Química e Biológica António Xavier (ITQB) MDPI - Multidisciplinary Digital Publishing Institute RUN |
| datacite.creators.creator.creatorName.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 |
| datacite.date.Accepted.fl_str_mv | 2021-03-01T00:00:00Z |
| datacite.date.available.fl_str_mv | 2021-07-09T22:18:00Z |
| datacite.date.embargoed.fl_str_mv | 2021-07-09T22:18:00Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.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 |
| datacite.titles.title.fl_str_mv | Modulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivatives |
| dc.contributor.none.fl_str_mv | Instituto de Tecnologia Química e Biológica António Xavier (ITQB) MDPI - Multidisciplinary Digital Publishing Institute RUN |
| dc.creator.none.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.date.Accepted.fl_str_mv | 2021-03-01T00:00:00Z |
| dc.date.available.fl_str_mv | 2021-07-09T22:18:00Z |
| dc.date.embargoed.fl_str_mv | 2021-07-09T22:18:00Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10362/120790 |
| dc.language.none.fl_str_mv | eng |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.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 |
| dc.title.fl_str_mv | Modulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivatives |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | 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. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://run.unl.pt/bitstreams/dffb1e9b-0e24-42ea-a15c-29ae5e1a86d1/download |
| id | run_8fba92a18a5525d2cb2d4e2dd4129744 |
| identifier.url.fl_str_mv | http://hdl.handle.net/10362/120790 |
| instacron_str | unl |
| institution | Universidade Nova de Lisboa |
| instname_str | Universidade Nova de Lisboa |
| language | eng |
| network_acronym_str | run |
| network_name_str | Repositório Institucional da UNL |
| oai_identifier_str | oai:run.unl.pt:10362/120790 |
| organization_str_mv | urn:organizationAcronym:unl |
| person_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 |
| publishDate | 2021 |
| reponame_str | Repositório Institucional da UNL |
| repository_id_str | urn:repositoryAcronym:run |
| service_str_mv | urn:repositoryAcronym:run |
| spelling | engenPhenylketonuria (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.application/pdfenModulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivativesLopes, 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, PaulaInstituto de Tecnologia Química e Biológica António Xavier (ITQB)MDPI - Multidisciplinary Digital Publishing InstituteHostingInstitutionOrganizationalRUNe-mailmailto:run@unl.ptrun@unl.ptISSNIsPartOf2218-273XURNIsPartOfPURE: 32441039URNIsPartOfPURE UUID: 729f9ed4-3c3a-4718-94fd-0b0df7bb469eURNIsPartOfScopus: 85102718258URNIsPartOfPubMed: 33808760DOIIsPartOf10.3390/biom110304622021-07-09T22:18:00Z2021-032021-03-01T00:00:00ZHandlehttp://hdl.handle.net/10362/120790http://purl.org/coar/access_right/c_abf2open accessActivity chaperonesDrug discoveryInherited metabolic disordersPharmacological chaperonesProtein drug interactionsProtein misfoldingBiochemistryMolecular BiologySDG 3 - Good Health and Well-being48517266 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://run.unl.pt/bitstreams/dffb1e9b-0e24-42ea-a15c-29ae5e1a86d1/download |
| 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 |
| status | SINGLETON |
| subject.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 |
| 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 | 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_facet | Activity chaperones Drug discovery Inherited metabolic disorders Pharmacological chaperones Protein drug interactions Protein misfolding Biochemistry Molecular Biology SDG 3 - Good Health and Well-being |
| url | http://hdl.handle.net/10362/120790 |
| visible | 1 |