Journal
ANALYTICAL CHEMISTRY
Volume 83, Issue 3, Pages 1048-1052Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ac1028424
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Funding
- National Cancer Institute [P01 CA48112]
- Office of Dietary Supplements [P50 AT00155]
- National Center for Complementary and Alternative Medicine of the National Institutes of Health
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [0922481] Funding Source: National Science Foundation
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Inhibitors of quinone reductase-2 (NQO2; QR-2) can have antimalarial activity and antitumor activities or can function as chemoprevention agents by preventing the metabolic activation of toxic quinones such as menadione. To expedite the search for new natural product inhibitors of QR-2, we developed a screening assay based on ultrafiltration liquid chromatography-mass spectrometry that is compatible with complex samples such as bacterial or botanical extracts. Human QR-2 was prepared recombinantly, and the known QR-2 inhibitor, resveratrol, was used as a positive control and as a competitive ligand to eliminate false positives Ultrafiltration LC-MS screening of extracts of marine sediment bacteria resulted in the discovery 4 tetrangulol methyl ether as an inhibitor of QR-2. When applied to the screening of hop extracts from the botanical, Humulus lupulus L., xanthohumol and xanthohumol D were identified as ligands of QR-2. Inhibition of QR-2 by these ligands was confirmed using a functional enzyme assay. Furthermore, binding of xanthohumol and xanthohumol D to the active site of QR-2 was confirmed using X-ray crystallography. Ultrafiltration LC-MS was shown to be a useful assay for the discovery of inhibitors of QR-2 in complex matrixes such as extracts of bacteria and botanicals.
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