Cargando…

Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase

Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 is a well characterized enzyme with high retinaldehyde reductase activity, involved in the development of several cancer types, the enzymatic activity and p...

Descripción completa

Detalles Bibliográficos
Autores principales: Giménez-Dejoz, Joan, Kolář, Michal H., Ruiz, Francesc X., Crespo, Isidro, Cousido-Siah, Alexandra, Podjarny, Alberto, Barski, Oleg A., Fanfrlík, Jindřich, Parés, Xavier, Farrés, Jaume, Porté, Sergio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519324/
https://www.ncbi.nlm.nih.gov/pubmed/26222439
http://dx.doi.org/10.1371/journal.pone.0134506
_version_ 1782383498016849920
author Giménez-Dejoz, Joan
Kolář, Michal H.
Ruiz, Francesc X.
Crespo, Isidro
Cousido-Siah, Alexandra
Podjarny, Alberto
Barski, Oleg A.
Fanfrlík, Jindřich
Parés, Xavier
Farrés, Jaume
Porté, Sergio
author_facet Giménez-Dejoz, Joan
Kolář, Michal H.
Ruiz, Francesc X.
Crespo, Isidro
Cousido-Siah, Alexandra
Podjarny, Alberto
Barski, Oleg A.
Fanfrlík, Jindřich
Parés, Xavier
Farrés, Jaume
Porté, Sergio
author_sort Giménez-Dejoz, Joan
collection PubMed
description Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 is a well characterized enzyme with high retinaldehyde reductase activity, involved in the development of several cancer types, the enzymatic activity and physiological role of AKR1B15 are still poorly known. Here, the purified recombinant enzyme has been subjected to substrate specificity characterization, kinetic analysis and inhibitor screening, combined with structural modeling. AKR1B15 is active towards a variety of carbonyl substrates, including retinoids, with lower k (cat) and K(m) values than AKR1B10. In contrast to AKR1B10, which strongly prefers all-trans-retinaldehyde, AKR1B15 exhibits superior catalytic efficiency with 9-cis-retinaldehyde, the best substrate found for this enzyme. With ketone and dicarbonyl substrates, AKR1B15 also shows higher catalytic activity than AKR1B10. Several typical AKR inhibitors do not significantly affect AKR1B15 activity. Amino acid substitutions clustered in loops A and C result in a smaller, more hydrophobic and more rigid active site in AKR1B15 compared with the AKR1B10 pocket, consistent with distinct substrate specificity and narrower inhibitor selectivity for AKR1B15.
format Online
Article
Text
id pubmed-4519324
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-45193242015-07-31 Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase Giménez-Dejoz, Joan Kolář, Michal H. Ruiz, Francesc X. Crespo, Isidro Cousido-Siah, Alexandra Podjarny, Alberto Barski, Oleg A. Fanfrlík, Jindřich Parés, Xavier Farrés, Jaume Porté, Sergio PLoS One Research Article Human aldo-keto reductase 1B15 (AKR1B15) is a newly discovered enzyme which shares 92% amino acid sequence identity with AKR1B10. While AKR1B10 is a well characterized enzyme with high retinaldehyde reductase activity, involved in the development of several cancer types, the enzymatic activity and physiological role of AKR1B15 are still poorly known. Here, the purified recombinant enzyme has been subjected to substrate specificity characterization, kinetic analysis and inhibitor screening, combined with structural modeling. AKR1B15 is active towards a variety of carbonyl substrates, including retinoids, with lower k (cat) and K(m) values than AKR1B10. In contrast to AKR1B10, which strongly prefers all-trans-retinaldehyde, AKR1B15 exhibits superior catalytic efficiency with 9-cis-retinaldehyde, the best substrate found for this enzyme. With ketone and dicarbonyl substrates, AKR1B15 also shows higher catalytic activity than AKR1B10. Several typical AKR inhibitors do not significantly affect AKR1B15 activity. Amino acid substitutions clustered in loops A and C result in a smaller, more hydrophobic and more rigid active site in AKR1B15 compared with the AKR1B10 pocket, consistent with distinct substrate specificity and narrower inhibitor selectivity for AKR1B15. Public Library of Science 2015-07-29 /pmc/articles/PMC4519324/ /pubmed/26222439 http://dx.doi.org/10.1371/journal.pone.0134506 Text en © 2015 Giménez-Dejoz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Giménez-Dejoz, Joan
Kolář, Michal H.
Ruiz, Francesc X.
Crespo, Isidro
Cousido-Siah, Alexandra
Podjarny, Alberto
Barski, Oleg A.
Fanfrlík, Jindřich
Parés, Xavier
Farrés, Jaume
Porté, Sergio
Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
title Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
title_full Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
title_fullStr Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
title_full_unstemmed Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
title_short Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
title_sort substrate specificity, inhibitor selectivity and structure-function relationships of aldo-keto reductase 1b15: a novel human retinaldehyde reductase
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519324/
https://www.ncbi.nlm.nih.gov/pubmed/26222439
http://dx.doi.org/10.1371/journal.pone.0134506
work_keys_str_mv AT gimenezdejozjoan substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT kolarmichalh substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT ruizfrancescx substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT crespoisidro substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT cousidosiahalexandra substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT podjarnyalberto substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT barskiolega substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT fanfrlikjindrich substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT paresxavier substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT farresjaume substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase
AT portesergio substratespecificityinhibitorselectivityandstructurefunctionrelationshipsofaldoketoreductase1b15anovelhumanretinaldehydereductase