Substrate Specificity, Inhibitor Selectivity and Structure-Function Relationships of Aldo-Keto Reductase 1B15 : a Novel Human Retinaldehyde Reductase
Giménez Dejoz, Joan (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Kolář, Michal H. (Academy of Sciences of the Czech Republic. Institute of Organic Chemistry and Biochemistry)
Ruiz, Francesc X. (Centre de Biologie Intégrative (Illkirch-Graffenstaden, França))
Crespo, Isidro (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Cousido-Siah, Alexandra (Centre de Biologie Intégrative (Illkirch-Graffenstaden, França))
Podjarny, Alberto (Centre de Biologie Intégrative (Illkirch-Graffenstaden, França))
Barski, Oleg A. (University of Louisville. School of Medicine)
Fanfrlík, Jindřich (Academy of Sciences of the Czech Republic. Institute of Organic Chemistry and Biochemistry)
Parés i Casasampera, Xavier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Farrés, Jaume (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Porté Orduna, Sergio (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2015
Abstract:	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 alltrans-retinaldehyde, AKR1B15 exhibits superior catalytic efficiency with 9-cisretinaldehyde, 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.
Grants:	Ministerio de Economía y Competitividad BFU2011-24176 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-795
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Cofactors (biochemistry) ; Enzyme inhibitors ; Isomers ; Aldehydes ; Mitochondria ; Steroids ; Enzyme purification ; Ketones
Published in:	PloS one, Vol. 10 Núm. 7 (July 2015) , p. e0134506, ISSN 1932-6203

DOI: 10.1371/journal.pone.0134506
PMID: 26222439

19 p, 2.5 MB

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