Article abstract
Nature Chemical Biology 4, 418 - 424 (2008)
Published online: 30 May 2008 | doi:10.1038/nchembio.94
Synthesis enables identification of the cellular target of leucascandrolide A and neopeltolide
Olesya A Ulanovskaya1, Jelena Janjic1, Masato Suzuki1, Simran S Sabharwal2, Paul T Schumacker2, Stephen J Kron3 & Sergey A Kozmin1
Abstract
Leucascandrolide A and neopeltolide are structurally homologous marine natural products that elicit potent antiproliferative profiles in mammalian cells and yeast. The scarcity of naturally available material has been a significant barrier to their biochemical and pharmacological evaluation. We developed practical synthetic access to this class of natural products that enabled the determination of their mechanism of action. We demonstrated effective cellular growth inhibition in yeast, which was substantially enhanced by substituting glucose with galactose or glycerol. These results, along with genetic analysis of determinants of drug sensitivity, suggested that leucascandrolide A and neopeltolide may inhibit mitochondrial ATP synthesis. Evaluation of the activity of the four mitochondrial electron transport chain complexes in yeast and mammalian cells revealed cytochrome bc1 complex as the principal cellular target. This result provided the molecular basis for the potent antiproliferative activity of this class of marine macrolides, thus identifying them as new biochemical tools for investigation of eukaryotic energy metabolism.
- Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
- Department of Pediatrics, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
- Ludwig Center for Metastasis Research, University of Chicago, 924 East 57th Street, Chicago, Illinois 60637, USA.
Correspondence to: Sergey A Kozmin1 e-mail: skozmin@uchicago.edu
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