Hop-derived compounds have been subjected to numerous biomedical studies investigating their impact on a wide range of pathologies. Isomerised bitter acids (isoadhumulone, isocohumulone and isohumulone) from hops, used in the brewing process of beer, are known to inhibit members of the aldo-keto-reductase superfamily. Aldo-keto-reductase 1B10 (AKR1B10) is upregulated in various types of cancer and has been reported to promote carcinogenesis. Inhibition of AKR1B10 appears to be an attractive means to specifically treat RAS-dependent malignancies. However, the closely related reductases AKR1A1 and AKR1B1, which fulfil important roles in the detoxification of endogenous and xenobiotic carbonyl compounds oftentimes crossreact with inhibitors designed to target AKR1B10. Accordingly, there is an ongoing search for selective AKR1B10 inhibitors that do not interact with endogeneous AKR1A1 and AKR1B1-driven detoxification systems. In this study, unisomerised α-acids (adhumulone, cohumulone and n-humulone) were separated and tested for their inhibitory potential on AKR1A1, AKR1B1 and AKR1B10. Also AKR1B10-mediated farnesal reduction was effectively inhibited by α-acid congeners with K_i-values ranging from 16.79 ± 1.33 µM (adhumulone) to 3.94 ± 0.33 µM (n-humulone). Overall, α-acids showed a strong inhibition with selectivity (115–137 fold) for AKR1B10. The results presented herein characterise hop-derived α-acids as a promising basis for the development of novel and selective AKR1B10-inhibitors.

The purpose of this study was to investigate the origin and function of the aldo‐keto reductase (AKR) superfamily as enzymes involved in the detoxification of xenobiotics. We used the cyanobacterium Sy ne chocystis sp. PCC 6803 as a model organism and sequence alignments to find bacterial AKRs with highest identity to human enzymes. Disappearance of NADPH was monitored spectrophotometrically to calculate enzymatic activity. The molecular weight of the native protein was determined by size exclusion chromatography. Substrate docking was performed by SwissDock. Sequence alignments identified the NADPH‐dependent AKR3G1 having 41.5 and 40% identity with the human enzymes AKR1B1 and AKR1B10, respectively. Highest enzymatic efficiency was observed with 4‐oxonon‐2‐enal (4‐ONE; k _cat /K _m , 561 s ^‐1 mM ^‐1 ) and 4‐hydroxynonenal (k _cat /K _m , 26.5 s ^‐1 mM ^‐1 ), respectively. P74308 is the most efficient enzyme for 4‐ONE discovered until now. Cooperativity of this monomeric enzyme was observed with some substrates. Enzyme inactivation or oligomerization as possible explanations for nonhyperbolic enzyme kinetics were ruled out by Selwyn's test and gel filtration. The role of the little investigated carbonyl‐reducing enzymes in detoxification seems to be in fact a very old process with rarely observed nonhyperbolic enzyme kinetics as an adaptation mechanism to higher concentrations of reactive oxygen species—Hintzpeter, J., Martin, H.‐J., Maser, E. Reduction of lipid peroxidation products and advanced glycation end‐product precursors by cyanobacterial aldo‐keto reductase AKR3G1—a founding member of the AKR3G subfamily. FASEB J. 29, 263–273 (2015). www.fasebj.org