Identifying and elucidating the roles of Y198N and Y204F mutations in the PAH enzyme through molecular dynamic simulations

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dc.authoridAslı Yenenler-Kutlu / 0000-0002-9169-388Xen_US
dc.authorscopusidAslı Yenenler-Kutlu / 57190336603
dc.authorwosidAslı Yenenler-Kutlu / AGG-7405-2022
dc.contributor.authorAslan, Tolga
dc.contributor.authorYenenler-Kutlu, Aslı
dc.contributor.authorGerlevik, Umut
dc.contributor.authorAktuğlu Zeybek, Ayşe Çiğdem
dc.contributor.authorKıykım, Ertuğrul
dc.contributor.authorSezerman, Osman Uğur
dc.date.accessioned2021-05-12T10:23:14Z
dc.date.available2021-05-12T10:23:14Z
dc.date.issued2021en_US
dc.departmentİstinye Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Biyoenformatik ve Genetik Bölümüen_US
dc.description.abstractABSTRACT Phenylketonuria is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase gene. In phenylketonuria causes various symptoms including severe mental retardation. PAH gene of a classical Phenylketonuria patient was sequenced, and two novel heterozygous mutations, p.Y198N and p.Y204F, were found. This study aimed to reveal the impacts of these variants on the structural stability of the PAH enzyme. In-silico analyses using prediction tools and molecular dynamics simulations were performed. Mutations were introduced to the wild type catalytic monomer and full length tetramer crystal structures. Variant pathogenicity analyses predicted p.Y198N to be damaging, and p.Y204F to be benign by some prediction tools and damaging by others. Simulations suggested p.Y198N mutation cause significant fluctuations in the spatial organization of two catalytic residues in the temperature accelerated MD simulations with the monomer and increased root-mean-square deviations in the tetramer structure. p.Y204F causes noticeable changes in the spatial positioning of T278 suggesting a possible segregation from the catalytic site in temperature accelerated MD simulations with the monomer. This mutation also leads to increased root-mean-square fluctuations in the regulatory domain which may lead to conformational change resulting in inhibition of dimerization and enzyme activation. Our study reports two novel mutations in the PAH gene and gives insight to their effects on the PAH activity. MD simulations did not yield conclusive results that explains the phenotype but gave plausible insight to possible effects which should be investigated further with in-silico and in-vitro studies to assess the roles of these mutations in etiology of PKU.en_US
dc.identifier.citationTolga Aslan, Aslı Yenenler-Kutlu, Umut Gerlevik, Ayşe Çiğdem Aktuğlu Zeybek, Ertuğrul Kıykım, Osman Uğur Sezerman & Necla Birgul Iyison (2021): Identifying and elucidating the roles of Y198N and Y204F mutations in the PAH enzyme through molecular dynamic simulations, Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2021.1921619en_US
dc.identifier.doi10.1080/07391102.2021.1921619en_US
dc.identifier.pmid33970801en_US
dc.identifier.scopus2-s2.0-85105997862en_US
dc.identifier.scopusqualityN/Aen_US
dc.identifier.urihttps://doi.org/10.1080/07391102.2021.1921619
dc.identifier.urihttps://hdl.handle.net/20.500.12713/1734
dc.identifier.wosWOS:000648757200001en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorYenenler-Kutlu, Aslı
dc.language.isoenen_US
dc.publisherTaylor And Francisen_US
dc.relation.ispartofJournal of Biomolecular Structure and Dynamicsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectPhenylketonuriaen_US
dc.subjectPhenylalanine Hydroxylaseen_US
dc.subjectPAHen_US
dc.subjectMolecular Dynamics Simulationen_US
dc.subjectHyperphenylalaninemiaen_US
dc.subjectNAMDen_US
dc.subjectVMDen_US
dc.titleIdentifying and elucidating the roles of Y198N and Y204F mutations in the PAH enzyme through molecular dynamic simulationsen_US
dc.typeArticleen_US

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