Computational Design of an Enzyme Catalyst for a Stereoselective Bimolecular Diels-Alder Reaction

Science  16 Jul 2010:
Vol. 329, Issue 5989, pp. 309-313
DOI: 10.1126/science.1190239

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The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.

  • * These authors contributed equally to this work.

  • Arzeda Corporation, 2722 Eastlake Avenue East, Suite 150, Seattle, WA 98102, USA.

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