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

0446845 - ÚOCHB 2016 RIV US eng J - Journal Article
Giménez-Dejoz, J. - Kolář, Michal H. - Ruiz, F. X. - Crespo, I. - Cousido-Siah, A. - Podjarny, A. - Barski, O. A. - Fanfrlík, Jindřich - Parés, X. - Farrés, J. - Porté, S.
Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15: A Novel Human Retinaldehyde Reductase.
PLoS ONE. Roč. 10, č. 7 (2015), e0134506/1-e0134506/19. ISSN 1932-6203. E-ISSN 1932-6203
Institutional support: RVO:61388963
Keywords : retinoic acid biosynthesis * site-directed mutagenesis * tumor marker AKR1B15
Subject RIV: CF - Physical ; Theoretical Chemistry
Impact factor: 3.057, year: 2015
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134506

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
Permanent Link: http://hdl.handle.net/11104/0248893