This title appears in the Scientific Report :
2016
Please use the identifier:
http://dx.doi.org/10.1371/journal.pone.0134506 in citations.
Please use the identifier: http://hdl.handle.net/2128/9847 in citations.
Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase
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...
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Personal Name(s): | 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 (Corresponding author) / Porté, Sergio (Corresponding author) | |
Contributing Institute: |
Computational Biomedicine; IAS-5 Computational Biomedicine; INM-9 |
Published in: | PLoS one, 10 (2015) 7, S. e0134506 - |
Imprint: |
Lawrence, Kan.
PLoS
2015
|
DOI: |
10.1371/journal.pone.0134506 |
PubMed ID: |
26222439 |
Document Type: |
Journal Article |
Research Program: |
Theory, modelling and simulation |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/9847 in citations.
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 kcat and Km 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. |