Potent Inhibition of Dinuclear Zinc(II) Peptidase, an Aminopeptidase from Aeromonas proteolytica, by 8-Quinolinol Derivatives: Inhibitor Design Based on Zn2+ Fluorophores, Kinetic, and X-ray Crystallographic Study
Kengo Hanaya, Miho Suetsugu, Shinya Saijo, Ichiro Yamato, and Shin Aoki[1]
Molecular Tour
The selective inhibition of an aminopeptidase from Aeromonas proteolytica (AAP), a dinuclear Zn2+ hydrolase, by 8-quinolinol (8-hydroxyquinoline, 8-HQ) derivatives is reported. Based on our findings about 8-HQ-based Zn2+ fluorophores, it was hypothesized that 8-HQ derivatives have the potential to function as specific inhibitors of Zn2+ enzymes, especially dinuclear Zn2+ hydrolases. Inhibitory assays of 8-HQ derivatives against AAP disclosed that the 8-HQ and 5-substituted 8-HQ′s are competitive inhibitors for AAP with inhibition constants (Ki) of 0.16—29 μM at pH 8.0. X-ray crystal structure analysis of an AAP–8-HQ complex (1.3 Å resolution) as well as fluorescence titrations of these drugs with AAP confirmed that 8-HQ binds to AAP in the “Pyr-out” mode, in which the hydroxide anion of 8-HQ bridges two Zn2+ (Zn1 and Zn2) in the active site of AAP and the nitrogen atom of 8-HQ coordinates to Zn1 (PDB code: 3vh9).
