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Brought to life: targeted activation of enzyme function with small molecules

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Journal of Chemical Biology

Abstract

Cell-permeable small molecules that are capable of activating particular enzymes would be invaluable tools for studying protein function in complex cell-signaling cascades. But, is it feasible to identify compounds that allow chemical–biology researchers to activate specific enzymes in a cellular context? In this review, we describe some recent advances in achieving targeted enzyme activation with small molecules. In addition to surveying progress in the identification and targeting of enzymes that contain natural allosteric-activation sites, we focus on recently developed protein-engineering strategies that allow researchers to render an enzyme of interest “activatable” by a pre-chosen compound. Three distinct strategies for targeting an engineered enzyme are discussed: direct chemical “rescue” of an intentionally inactivated enzyme, activation of an enzyme by targeting a de novo small-molecule-binding site, and the generation of activatable enzymes via fusion of target enzymes to previously characterized small-molecule-binding domains.

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Acknowledgments

The authors thank the National Institutes of Health (1 R15 GM071388-01A1) and Research Corporation (CC6372) for research support.

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Authors and Affiliations

  1. Department of Chemistry, Amherst College, Amherst, MA, 01002, USA

    Anthony C. Bishop & Vincent L. Chen

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  1. Anthony C. Bishop
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  2. Vincent L. Chen
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Correspondence to Anthony C. Bishop.

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Bishop, A.C., Chen, V.L. Brought to life: targeted activation of enzyme function with small molecules. J Chem Biol 2, 1–9 (2009). https://doi.org/10.1007/s12154-008-0012-4

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  • DOI: https://doi.org/10.1007/s12154-008-0012-4

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