Studies toward the unique pederin family member psymberin

Structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin

Cheng Yang Wu, Yu Feng, Eduardo R. Cardenas, Noelle Williams, Paul E. Floreancig, Jef K. De Brabander, Michael G. Roth

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)18998-19003
Number of pages6
JournalJournal of the American Chemical Society
Volume134
Issue number46
DOIs
StatePublished - Nov 21 2012

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Structure-Activity Relationship
Molecular Biology
Proteins
Bearings (structural)
Stereochemistry
Gene encoding
Protein Biosynthesis
Cytotoxicity
Bioactivity
Amides
Assays
pederin
psymberin
Genetics
Aptitude
Irritants
Ribosomal Proteins
Caenorhabditis elegans
Biological Products
Point Mutation

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

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title = "Studies toward the unique pederin family member psymberin: Structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin",
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.",
author = "Wu, {Cheng Yang} and Yu Feng and Cardenas, {Eduardo R.} and Noelle Williams and Floreancig, {Paul E.} and {De Brabander}, {Jef K.} and Roth, {Michael G.}",
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T2 - Structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin

AU - Wu, Cheng Yang

AU - Feng, Yu

AU - Cardenas, Eduardo R.

AU - Williams, Noelle

AU - Floreancig, Paul E.

AU - De Brabander, Jef K.

AU - Roth, Michael G.

PY - 2012/11/21

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N2 - 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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