title: Structure-Dependent Deconjugation of Flavonoid Glucuronides by Human β-Glucuronidase - In Vitro and In Silico Analyses.
abstract: Flavonoid glycosides are extensively metabolized to glucuronidated compounds after oral intake. Recently, a cleavage of quercetin glucuronides by β-glucuronidase has been found. To characterize the deglucuronidation reaction and its structural prerequisites among the flavonoid subtypes more precisely, four flavonol glucuronides with varying glucuronidation positions, five flavone 7-O-glucuronides with varying A- and B-ring substitution as well as one flavanone- and one isoflavone-7-O-glucuronide were analyzed in a human monocytic cell line. Investigation of the deglucuronidation rates by HPLC revealed a significant influence of the glucuronidation position on enzyme activity for flavonols. Across the flavonoid subtypes, the C-ring saturation also showed a significant influence on deglucuronidation, whereas A- and B-ring variations within the flavone-7-O-glucuronides did not affect the enzymes' activity. Results were compared to computational binding studies on human β-glucuronidase. Additionally, molecular modeling and dynamic studies were performed to obtain detailed insight into the binding and cleavage mode of the substrate at the active site of the human β-glucuronidase.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Untergehrer
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bücherl
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Wittmann
authors.affiliation: Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Strasser
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Jürgenliemk
mesh_terms: D002851:Chromatography, High Pressure Liquid; D044950:Flavanones / Q000737:chemistry; D047309:Flavones / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry*; D044948:Flavonols / Q000737:chemistry; D005966:Glucuronidase / Q000737:chemistry*; D020719:Glucuronides / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009000:Monocytes / Q000378:metabolism; D011794:Quercetin / Q000737:chemistry*
chemical_list: D044950:Flavanones; D047309:Flavones; D005419:Flavonoids; D044948:Flavonols; D020719:Glucuronides; D011794:Quercetin; D005966:Glucuronidase; C043562:flavone; C028610:flavanone