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Inhibition of inositol phosphorylceramide synthase by the cyclic peptide aureobasidin A.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Aeed, Paul A. Young, Casey L. Nagiec, Marek M. Elhammer, Ake P. |
| Copyright Year | 2009 |
| 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. |
| Starting Page | 496 |
| Ending Page | 504 |
| Page Count | 9 |
| File Format | PDF HTM / HTML |
| DOI | 10.1128/AAC.00633-08 |
| PubMed reference number | 19047657 |
| Journal | Medline |
| Volume Number | 53 |
| Issue Number | 2 |
| Alternate Webpage(s) | https://www.st-va.ncbi.nlm.nih.gov/pmc/articles/PMC2630602/pdf/0633-08.pdf |
| Alternate Webpage(s) | http://aac.asm.org/content/53/2/496.full.pdf |
| Alternate Webpage(s) | https://doi.org/10.1128/AAC.00633-08 |
| Journal | Antimicrobial agents and chemotherapy |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
