{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:42:36Z","timestamp":1761061356782,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/04138\/2020, UIDP\/04138\/2020, LISBOA-01-0145-FEDER-007344, Research projects PTDC\/MED-QUI\/29712\/2017 and PTDC\/QUI-QOR\/29967\/2017; and Principal Researcher grant CEECIND\/03143\/2017"],"award-info":[{"award-number":["UIDB\/04138\/2020, UIDP\/04138\/2020, LISBOA-01-0145-FEDER-007344, Research projects PTDC\/MED-QUI\/29712\/2017 and PTDC\/QUI-QOR\/29967\/2017; and Principal Researcher grant CEECIND\/03143\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020","doi-asserted-by":"publisher","award":["Grant agreement No 810856"],"award-info":[{"award-number":["Grant agreement No 810856"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Marie-Sklodowska Curie ITN","award":["ProteinConjugates"],"award-info":[{"award-number":["ProteinConjugates"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/biom11030462","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T11:18:38Z","timestamp":1616152718000},"page":"462","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives"],"prefix":"10.3390","volume":"11","author":[{"given":"Raquel R.","family":"Lopes","sequence":"first","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"given":"Catarina S.","family":"Tom\u00e9","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, Av. da Rep\u00fablica, 2780-157 Oeiras, Portugal"},{"name":"Instituto de Biologia Experimental e Tecnol\u00f3gica, Quinta do Marqu\u00eas, 2780-155 Oeiras, Portugal"}]},{"given":"Roberto","family":"Russo","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"given":"Roberta","family":"Paterna","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"given":"Jo\u00e3o","family":"Leandro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2414-9064","authenticated-orcid":false,"given":"Nuno R.","family":"Candeias","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Natural Sciences, Tampere University, Korkeakoulunkatu 8, 33101 Tampere, Finland"},{"name":"LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6799-2740","authenticated-orcid":false,"given":"L\u00eddia M. D.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4124-6237","authenticated-orcid":false,"given":"Miguel","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, Av. da Rep\u00fablica, 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6672-3610","authenticated-orcid":false,"given":"Pedro M. F.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Instituto de Biologia Experimental e Tecnol\u00f3gica, Quinta do Marqu\u00eas, 2780-155 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-9181","authenticated-orcid":false,"given":"Rita C.","family":"Guedes","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"given":"Jo\u00e3o B.","family":"Vicente","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, Av. da Rep\u00fablica, 2780-157 Oeiras, Portugal"}]},{"given":"Pedro M. P.","family":"Gois","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2946-9342","authenticated-orcid":false,"given":"Paula","family":"Leandro","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1750-1172-7-39","article-title":"A generalizable pre-clinical research approach for orphan disease therapy","volume":"7","author":"Beaulieu","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s10545-016-0005-3","article-title":"Small molecules as therapeutic agents for inborn errors of metabolism","volume":"40","author":"Matalonga","year":"2017","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1007\/s10545-014-9701-z","article-title":"Innovative strategies to treat protein misfolding in inborn errors of metabolism: Pharmacological chaperones and proteostasis regulators","volume":"37","author":"Muntau","year":"2014","journal-title":"J. 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