Fig. 5: Isoxazole 1 is an uncompetitive inhibitor of CnAcs1.
From: Discovery and mechanism of a highly selective, antifungal acetyl-CoA synthetase inhibitor
A Schematic of the two-step reaction catalyzed by Acs and the conformational changes that occur during the reaction. APO indicates an enzyme without substrate or product bound. AD indicates conformation associated with the adenylation reaction that generates the Ac-AMP intermediate. TE indicates the conformation associated with the thio-esterification reaction of Ac-AMP with CoA to yield AcCoA. CTD indicates the C-terminal domain of the protein that undergoes rearrangement through the course of the reaction. B, C Determination of isoxazole 1 Ki values for ATP and CoA substrates and goodness-of-fit (R2) values for an uncompetitive model of inhibition using non-linear regression analysis. The heat scheme shows the color-concentration correlations for the reaction plots. D, E Lineweaver-Burke plots for isoxazole 1 with ATP and CoA. F, G Plot of Km v isoxazole 1 concentration for ATP and CoA. The R2 values for the goodness-of-fit of the non-linear regression were 0.92 and 0.91 for the ATP (F) and CoA (G), respectively. Source data are provided as a Source data file.
