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PMID:19047657
| Citation |
Aeed, PA, Young, CL, Nagiec, MM and Elhammer, AP (2009) Inhibition of inositol phosphorylceramide synthase by the cyclic peptide aureobasidin A. Antimicrob. Agents Chemother. 53:496-504 |
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| Abstract |
By using a detergent-washed membrane preparation, the interaction of the fungal natural product inhibitor aureobasidin A (AbA) with inositol phosphorylceramide synthase (IPC synthase) was studied by kinetic analysis of wild-type and mutant enzyme-catalyzed reactions. AbA inhibited the wild-type enzyme from both Candida albicans and Saccharomyces cerevisiae in an irreversible, time-dependent manner, with apparent K(i) values of 183 and 234 pM, respectively. Three synthetic chemistry-derived AbA derivatives, PHA-533179, PHA-556655, and PHA-556656, had affinities 4 to 5 orders of magnitude lower and were reversible inhibitors that competed with the donor substrate phosphatidylinositol (PI). AbA was a reversible, apparently noncompetitive inhibitor, with a K(i) of 1.4 microM, of the IPC synthase from an AbA-resistant S. cerevisiae mutant. The K(m) values for both substrates (ceramide and PI) were similar when they interacted with the mutant and the wild-type enzymes. By contrast, the V(max) for the mutant enzyme was less than 10% of that for the wild-type enzyme. A comparison of the results obtained with AbA with those obtained with two other natural products inhibitors, rustmicin and khafrefungin, revealed that while rustmicin appeared to be a reversible, noncompetitive inhibitor of the wild-type enzyme, with a K(i) of 16.0 nM, khafrefungin had the kinetic properties of a time-dependent inhibitor and an apparent K(i) of 0.43 nM. An evaluation of the efficiencies of these compounds as inhibitors of the mutant enzyme revealed for both a drop in the apparent affinity for the enzyme of more than 2 orders of magnitude. |
| Links |
PubMed PMC2630602 Online version:10.1128/AAC.00633-08 |
| Keywords |
Algorithms; Antifungal Agents/pharmacology; Candida albicans/drug effects; Depsipeptides/pharmacology; Drug Resistance, Fungal; Enzyme Inhibitors/pharmacology; Glycolipids/pharmacology; Hexosyltransferases/antagonists & inhibitors; Kinetics; Saccharomyces cerevisiae/drug effects; Time Factors |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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