Computational design of an enzyme catalyst for a stereoselective bimolecular diels-alder reaction

Justin Siegel, Alexandre Zanghellini, Helena M. Lovick, Gert Kiss, Abigail R. Lambert, Jennifer L. St.Clair, Jasmine L. Gallaher, Donald Hilvert, Michael H. Gelb, Barry L. Stoddard, Kendall N. Houk, Forrest E. Michael, David Baker

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)309-313
Number of pages5
JournalScience
Volume329
Issue number5989
DOIs
StatePublished - Jul 16 2010
Externally publishedYes

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Cite this

Siegel, J., Zanghellini, A., Lovick, H. M., Kiss, G., Lambert, A. R., St.Clair, J. L., Gallaher, J. L., Hilvert, D., Gelb, M. H., Stoddard, B. L., Houk, K. N., Michael, F. E., & Baker, D. (2010). Computational design of an enzyme catalyst for a stereoselective bimolecular diels-alder reaction. Science, 329(5989), 309-313. https://doi.org/10.1126/science.1190239