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Small-molecule activators of a proenzyme

Academic Article
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Overview

authors

  • Wolan, Dennis
  • Zorn, J. A.
  • Gray, D. C.
  • Wells, J. A.

publication date

  • November 2009

journal

  • Science  Journal

abstract

  • Virtually all of the 560 human proteases are stored as inactive proenyzmes and are strictly regulated. We report the identification and characterization of the first small molecules that directly activate proenzymes, the apoptotic procaspases-3 and -6. It is surprising that these compounds induce autoproteolytic activation by stabilizing a conformation that is both more active and more susceptible to intermolecular proteolysis. These procaspase activators bypass the normal upstream proapoptotic signaling cascades and induce rapid apoptosis in a variety of cell lines. Systematic biochemical and biophysical analyses identified a cluster of mutations in procaspase-3 that resist small-molecule activation both in vitro and in cells. Compounds that induce gain of function are rare, and the activators reported here will enable direct control of the executioner caspases in apoptosis and in cellular differentiation. More generally, these studies presage the discovery of other proenzyme activators to explore fundamental processes of proenzyme activation and their fate-determining roles in biology.

subject areas

  • Animals
  • Apoptosis
  • Benzopyrans
  • Biocatalysis
  • Caspase 3
  • Caspase 6
  • Caspase Inhibitors
  • Catalytic Domain
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cells, Cultured
  • Enzyme Activation
  • Enzyme Activators
  • Enzyme Inhibitors
  • Enzyme Precursors
  • Granzymes
  • Humans
  • Imidazoles
  • Kinetics
  • Mice
  • Molecular Structure
  • Mutagenesis
  • Pyridines
  • Signal Transduction
  • Small Molecule Libraries
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Identity

PubMed Central ID

  • PMC2886848

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1177585

PubMed ID

  • 19892984
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Additional Document Info

start page

  • 853

end page

  • 858

volume

  • 326

issue

  • 5954

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