Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms

Detalhes bibliográficos
Autor(a) principal: Mota, Cristiano
Data de Publicação: 2019
Outros Autores: Esmaeeli, Mariam, Coelho, Catarina, Santos-Silva, Teresa, Wolff, Martin, Foti, Alessandro, Leimkühler, Silke, Romão, Maria João
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: https://doi.org/10.1002/2211-5463.12617
Resumo: This work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019), Project PTDC/BBB-BEP/1185/2014 and Grant SFRH/BPD/ 84581/2012 (CC). SL thanks the Deutsche Forschungsge-meinschaft (DFG) for the support with Grant LE1171/8-3. The ESRF staff are also acknowledged, in particular ID30B beamline staff (ESRF, Grenoble).
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spelling Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphismshuman aldehyde oxidasemolybdenum cofactorsingle nucleotide polymorphismxanthine oxidaseBiochemistry, Genetics and Molecular Biology(all)This work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019), Project PTDC/BBB-BEP/1185/2014 and Grant SFRH/BPD/ 84581/2012 (CC). SL thanks the Deutsche Forschungsge-meinschaft (DFG) for the support with Grant LE1171/8-3. The ESRF staff are also acknowledged, in particular ID30B beamline staff (ESRF, Grenoble).Human aldehyde oxidase (hAOX1) is a molybdenum enzyme with high toxicological importance, but its physiological role is still unknown. hAOX1 metabolizes different classes of xenobiotics and is one of the main drug-metabolizing enzymes in the liver, along with cytochrome P450. hAOX1 oxidizes and inactivates a large number of drug molecules and has been responsible for the failure of several phase I clinical trials. The interindividual variability of drug-metabolizing enzymes caused by single nucleotide polymorphisms (SNPs) is highly relevant in pharmaceutical treatments. In this study, we present the crystal structure of the inactive variant G1269R, revealing the first structure of a molybdenum cofactor (Moco)-free form of hAOX1. These data allowed to model, for the first time, the flexible Gate 1 that controls access to the active site. Furthermore, we inspected the thermostability of wild-type hAOX1 and hAOX1 with various SNPs (L438V, R1231H, G1269R or S1271L) by CD spectroscopy and ThermoFAD, revealing that amino acid exchanges close to the Moco site can impact protein stability up to 10 °C. These results correlated with biochemical and structural data and enhance our understanding of hAOX1 and the effect of SNPs in the gene encoding this enzyme in the human population. Enzymes: Aldehyde oxidase (EC1.2.3.1); xanthine dehydrogenase (EC1.17.1.4); xanthine oxidase (EC1.1.3.2). Databases: Structural data are available in the Protein Data Bank under the accession number 6Q6Q.DQ - Departamento de QuímicaUCIBIO - Applied Molecular Biosciences UnitRUNMota, CristianoEsmaeeli, MariamCoelho, CatarinaSantos-Silva, TeresaWolff, MartinFoti, AlessandroLeimkühler, SilkeRomão, Maria João2019-07-15T22:41:15Z2019-05-012019-05-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article10application/pdfhttps://doi.org/10.1002/2211-5463.12617eng2211-5463PURE: 13349087http://www.scopus.com/inward/record.url?scp=85065033277&partnerID=8YFLogxKhttps://doi.org/10.1002/2211-5463.12617info: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:RCAAP2024-03-11T04:34:32Zoai:run.unl.pt:10362/75565Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:35:31.655255Repositório 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 Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
title Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
spellingShingle Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
Mota, Cristiano
human aldehyde oxidase
molybdenum cofactor
single nucleotide polymorphism
xanthine oxidase
Biochemistry, Genetics and Molecular Biology(all)
title_short Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
title_full Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
title_fullStr Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
title_full_unstemmed Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
title_sort Human aldehyde oxidase (hAOX1): structure determination of the Moco-free form of the natural variant G1269R and biophysical studies of single nucleotide polymorphisms
author Mota, Cristiano
author_facet Mota, Cristiano
Esmaeeli, Mariam
Coelho, Catarina
Santos-Silva, Teresa
Wolff, Martin
Foti, Alessandro
Leimkühler, Silke
Romão, Maria João
author_role author
author2 Esmaeeli, Mariam
Coelho, Catarina
Santos-Silva, Teresa
Wolff, Martin
Foti, Alessandro
Leimkühler, Silke
Romão, Maria João
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv DQ - Departamento de Química
UCIBIO - Applied Molecular Biosciences Unit
RUN
dc.contributor.author.fl_str_mv Mota, Cristiano
Esmaeeli, Mariam
Coelho, Catarina
Santos-Silva, Teresa
Wolff, Martin
Foti, Alessandro
Leimkühler, Silke
Romão, Maria João
dc.subject.por.fl_str_mv human aldehyde oxidase
molybdenum cofactor
single nucleotide polymorphism
xanthine oxidase
Biochemistry, Genetics and Molecular Biology(all)
topic human aldehyde oxidase
molybdenum cofactor
single nucleotide polymorphism
xanthine oxidase
Biochemistry, Genetics and Molecular Biology(all)
description This work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT/MCTES (UID/Multi/04378/2019), Project PTDC/BBB-BEP/1185/2014 and Grant SFRH/BPD/ 84581/2012 (CC). SL thanks the Deutsche Forschungsge-meinschaft (DFG) for the support with Grant LE1171/8-3. The ESRF staff are also acknowledged, in particular ID30B beamline staff (ESRF, Grenoble).
publishDate 2019
dc.date.none.fl_str_mv 2019-07-15T22:41:15Z
2019-05-01
2019-05-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://doi.org/10.1002/2211-5463.12617
url https://doi.org/10.1002/2211-5463.12617
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 2211-5463
PURE: 13349087
http://www.scopus.com/inward/record.url?scp=85065033277&partnerID=8YFLogxK
https://doi.org/10.1002/2211-5463.12617
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10
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dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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