title: D-Alanine:D-alanine ligase as a new target for the flavonoids quercetin and apigenin.
abstract: Flavonoids are polyphenolic compounds that are ubiquitous in nature. They possess varied promising properties for medical use. Quercetin (3,3',4',5,7-pentahydroxyflavone) and apigenin (4',5,7-trihydroxyflavone) are two representative flavonoids, both of which have been reported to possess antibacterial activity by acting on multiple targets. Here, we determined that d-alanine:d-alanine ligase (Ddl) is another new target for quercetin and apigenin. Kinetic analysis indicated that these two flavonoids function as reversible inhibitors that are competitive with the substrate ATP of Ddl, whereas they are non-competitive with the other substrate d-Ala. The fact that quercetin showed lower 50% inhibitory concentration (IC(50)) and inhibitor binding constant (K(i)) values than apigenin against both the Helicobacter pylori Ddl and the Escherichia coli DdlB implies that the two additional hydroxyls on the flavone skeleton of quercetin in structure might facilitate its inhibitory activity and binding affinity to Ddl. This work is expected to help shed more light on the potential antibacterial mechanism of flavonoids.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Dalei
authors.initials: D
authors.lastname: Wu
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Kong
authors.forename: Cong
authors.initials: C
authors.lastname: Han
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Lihong
authors.initials: L
authors.lastname: Hu
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D047310:Apigenin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects; D016480:Helicobacter pylori / Q000187:drug effects; D017665:Hydroxyl Radical / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D016877:Oxidants / Q000494:pharmacology; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D011794:Quercetin / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D016877:Oxidants; D017665:Hydroxyl Radical; D047310:Apigenin; D000255:Adenosine Triphosphate; D011794:Quercetin; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase