Inhibition of inositol phosphorylceramide synthase by the cyclic peptide aureobasidin A.

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Aeed PA, Young CL, Nagiec MM, Elhammer AP

Inhibition of inositol phosphorylceramide synthase by the cyclic peptide aureobasidin A.

Antimicrob Agents Chemother. 2009 Feb;53(2):496-504. doi: 10.1128/AAC.00633-08. Epub 2008 Dec 1.

PubMed ID

19047657 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Drugs

Basifungin

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Basifungin	Inositol phosphorylceramide synthase	Protein	Yeast	Yes	Inhibitor	Details

Polypeptides

Name	UniProt ID
Inositol phosphorylceramide synthase	O13332	Details