Abstract
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 Ki-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.
Highlights
Inpharmacology and nutritional medicine, beer and its constituents have been subject to numerous epidemiological and molecular studies, not least in order to evaluate the manifold effects of its main flavouring ingredient, the female inflorescences of the hop plant (Humulus lupulus)
C-terminal cysteines of the target proteins [10,11]. These isoprenoids fall within the specific substrate spectrum of aldo-keto reductase member 1B10 (AKR1B10), an NADPH-dependent oxidoreductase that has been shown to play a pivotal role in the prenylation-dependent activation of KRAS and RAS-like proteins by mediating the reduction of geranylgeranyl and farnesal to their respective alcohols [9,12]
Two other members of the same superfamily AKR1B1 and AKR1A1 are closely related to Aldo-keto-reductase 1B10 (AKR1B10), sharing around 71% and 48% of sequence identity on the protein level, respectively [25]
Summary
In (phyto-)pharmacology and nutritional medicine, beer and its constituents have been subject to numerous epidemiological and molecular studies, not least in order to evaluate the manifold effects of its main flavouring ingredient, the female inflorescences of the hop plant (Humulus lupulus). C-terminal cysteines of the target proteins [10,11] These isoprenoids fall within the specific substrate spectrum of aldo-keto reductase member 1B10 (AKR1B10), an NADPH-dependent oxidoreductase that has been shown to play a pivotal role in the prenylation-dependent activation of KRAS and RAS-like proteins by mediating the reduction of geranylgeranyl and farnesal to their respective alcohols [9,12]. Two other members of the same superfamily AKR1B1 and AKR1A1 are closely related to AKR1B10, sharing around 71% and 48% of sequence identity on the protein level, respectively [25] They are both involved in other detoxifying mechanisms and are necessary to maintain homeostasis of the glucose metabolism [26].
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