Retinaldehyde is a substrate for human aldo-keto reductases of the 1C subfamily

F. Xavier Ruiz, Sergio Porté, Oriol Gallego, Armando Moro, Albert Ardèvol, Alberto Del Río-Espínola, Carme Rovira, Jaume Farrés, Xavier Parés

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29 Citas (Scopus)

Resumen

Human AKR (aldo-keto reductase) 1C proteins (AKR1C1-AKR1C4) exhibit relevant activity with steroids, regulating hormone signalling at the pre-receptor level. In the present study, investigate the activity of the four human AKR1C enzymes with retinol and retinaldehyde. All of the enzymes except AKR1C2 showed retinaldehyde reductase activity with low Km values (∼1 μM). The kcat values were also low (0.18-0.6 min -1), except for AKR1C3 reduction of 9-cis-retinaldehyde whose k cat was remarkably higher (13 min-1). Structural modelling of the AKR1C complexes with 9-cis-retinaldehyde indicated a distinct conformation of Trp227, caused by changes in residue 226 that may contribute to the activity differences observed. This was partially supported by the kinetics of the AKR1C3 mutant. Retinol/retinaldehyde conversion, combined with the use of the inhibitor flufenamic acid, indicated a relevant role for endogenous AKR1Cs in retinaldehyde reduction in MCF-7 breast cancer cells. Overexpression of AKR1C proteins depleted RA (retinoic acid) transactivation in HeLa cells treated with retinol. Thus AKR1Cs may decrease RA levels in vivo. Finally, by using lithocholic acid as an AKR1C3 inhibitor and UVI2024 as an RA receptor antagonist, we provide evidence that the pro-proliferative action of AKR1C3 in HL-60 cells involves the RA signalling pathway and that this is in part due to the retinaldehyde reductase activity of AKR1C3. © The Authors Journal compilation © 2011 Biochemical Society.
Idioma originalInglés
Páginas (desde-hasta)335-344
PublicaciónBiochemical Journal
Volumen440
DOI
EstadoPublicada - 15 dic 2011

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