Untergehrer Monika, Bücherl Daniel, Wittmann Hans-Joachim, Strasser Andrea, Heilmann Jörg, Jürgenliemk Guido
Department of Pharmaceutical Biology, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Regensburg, Germany.
Planta Med. 2015 Aug;81(12-13):1182-9. doi: 10.1055/s-0035-1545980. Epub 2015 May 27.
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.
黄酮类糖苷在口服摄入后会广泛代谢为葡萄糖醛酸化化合物。最近，发现β-葡萄糖醛酸酶可裂解槲皮素葡萄糖醛酸苷。为了更精确地表征黄酮类亚型中去葡萄糖醛酸化反应及其结构前提条件，在人单核细胞系中分析了四种具有不同葡萄糖醛酸化位置的黄酮醇葡萄糖醛酸苷、五种具有不同A环和B环取代基的黄酮7-O-葡萄糖醛酸苷以及一种黄烷酮-7-O-葡萄糖醛酸苷和一种异黄酮-7-O-葡萄糖醛酸苷。通过高效液相色谱法对去葡萄糖醛酸化速率的研究表明，葡萄糖醛酸化位置对黄酮醇的酶活性有显著影响。在所有黄酮类亚型中，C环饱和度对去葡萄糖醛酸化也有显著影响，而黄酮7-O-葡萄糖醛酸苷中A环和B环的变化并不影响酶的活性。将结果与人β-葡萄糖醛酸酶的计算结合研究进行了比较。此外，还进行了分子建模和动力学研究，以深入了解底物在人β-葡萄糖醛酸酶活性位点的结合和裂解模式。
