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Modulation of human phenylalanine hydroxylase by 3-hydroxyquinolin-2(1h)-one derivatives

DOI: 10.3390/biom11030462 DOI Help

Authors: Raquel R. Lopes (Universidade de Lisboa) , Catarina S. Tomé (Universidade de Lisboa; Universidade Nova de Lisboa; Instituto de Biologia Experimental e Tecnológica) , Roberto Russo (Universidade de Lisboa) , Roberta Paterna (Universidade de Lisboa) , João Leandro (Universidade de Lisboa) , Nuno R. Candeias (Tampere University; University of Aveiro) , Lídia M. D. Gonçalves (Universidade de Lisboa) , Miguel Teixeira (Universidade Nova de Lisboa) , Pedro M. F. Sousa (Instituto de Biologia Experimental e Tecnológica) , Rita C. Guedes (Universidade de Lisboa) , João B. Vicente (Universidade Nova de Lisboa) , Pedro M. P. Gois (Universidade de Lisboa) , Paula Leandro (Universidade de Lisboa)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biomolecules , VOL 11

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 20161

Open Access Open Access

Abstract: 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.

Journal Keywords: protein misfolding; drug discovery; inherited metabolic disorders; protein drug interactions; pharmacological chaperones; activity chaperones

Subject Areas: Biology and Bio-materials, Medicine

Instruments: B21-High Throughput SAXS


Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Non-Communicable Diseases

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)