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

Overview & Synopsis

Human aldo-keto reductase 1C proteins (AKR1C1-AKR1C4) exhibit relevant activity with steroids, regulating hormone signaling at pre-receptor level. We here investigate the activity of the four human AKR1C enzymes with retinol and retinaldehyde. All 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 with 9‑cis-retinaldehyde whose kcat was remarkably higher (13 min−1). Structural modeling of the AKR1C complexes with 9-cis-retinaldehyde indicated a distinct conformation of Trp-227, originated by changes in residue 226, which may contribute to activity differences. This was partially supported by the kinetics of the AKR1C3 R226P mutant. Retinol/retinaldehyde conversion, combined with the use of the inhibitor flufenamic acid, indicated a relevant role of endogenous AKR1Cs in retinaldehyde reduction in MCF-7 breast cancer cells. Overexpression of AKR1C proteins depleted retinoic acid (RA) trans-activation 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 signaling pathway and that this is in part due to the retinaldehyde reductase activity of AKR1C3.