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      Studies toward the unique pederin family member psymberin: structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin.

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          Abstract

          Psymberin is the only member of the pederin natural product family that contains a dihydroisocoumarin side chain. Structural modifications of psymberin uncoupled inhibition of protein translation from cytotoxicity, suggesting that psymberin has more than one bioactivity. A forward genetic screen in Caenorhabditis elegans was conducted to identify the molecular target(s) of psymberin. Multiple independent psymberin-resistant mutants were isolated, each containing the same point mutation in a gene encoding a ribosomal protein. However, a psymberin-resistant mutant strain bearing this mutation was not cross-resistant to the pederin family member mycalamide A, which binds to the archaeal form of the same protein. Thus, two pederin family members likely differ in how they bind the same molecular target. The accumulation of psymberin in cells was sensitive to the stereochemistry of the amide side chain at C4 or C8 and the presence of the dihydroisocoumarin side chain. The observation that psymberin diastereomers or dihydroisocoumarin-truncated analogs lose all cytotoxic activity while retaining the ability to inhibit protein translation in a cell-free in vitro assay can be explained in the context of these differential cell uptake issues. Finally, we also demonstrate that the blistering activity associated with pederin and other members of the family is not due to their protein synthesis inhibiting activity. Unlike pederin and mycalamide, psymberin does not display irritant or blistering activity.

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          Author and article information

          Journal
          J. Am. Chem. Soc.
          Journal of the American Chemical Society
          American Chemical Society (ACS)
          1520-5126
          0002-7863
          Nov 21 2012
          : 134
          : 46
          Affiliations
          [1 ] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
          Article
          NIHMS418454
          10.1021/ja3057002
          3504174
          23088155
          7ce52e87-2c79-4c65-9b69-251fddbd299d
          History

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