UW Chemistry professors Michael Gelb and Forrest Michael, in collaboration with Prof. David Baker (UW Biochemistry), have engineered an artificial enzyme capable of catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. Their findings were reported July 16 in Science. The team of collaborators used computer modeling to screen over 10 billion possible protein backbone geometries for the ones that could support the right combination of active sites and catalytic residues. From this list, and further optimization, 84 de novo designs were selected for experimental work. Ultimately, two of the designed enzymes showed the ability to catalyze the Diels-Alder reaction.
The Diels-Alder reaction is one of the cornerstones of synthetic chemistry and no naturally occurring enzymes have been shown to catalyze it. Broader application of de novo enzyme design should be significantly useful in synthetic chemistry.
The authors of the paper also include Justin Siegel (graduate student in biochemistry, UW), Alexandre Zanghellini (graduate student in biochemistry, UW), Helena Lovick (graduate student in chemistry, UW), Gert Kiss (graduate student in chemistry, UCLA), Abigail Lambert (former graduate student with Prof. Stoddard), Jennifer St. Clair (Dept. of Biochemistry, UW), Jasmine Gallaher (lab technician, Baker lab), Barry Stoddard (Professor at Fred Hutchinson Cancer Research Center in Seattle), Don Hilvert (Professor of Chemistry, ETH Zurich), Michael Gelb (Professor of Chemistry, UW), Ken Houk (Professor of Chemistry, UCLA), Forrest Michael (Associate Professor of Chemistry, UW), David Baker (Professor of Biochemistry, UW).
Picture: UW graduate student Justin Siegel, professor Forrest Michael, professor Michael Gelb and post-doctoral fellow Alexandre Zanghellini (Steve Ringman / The Seattle Times).
J. B. Siegel, A. Zanghellini, H. M. Lovick, G. Kiss, A. R. Lambert, J. L. St. Clair, J. L. Gallaher, D. Hilvert, M. H. Gelb, B. L. Stoddard, K. N. Houk, F. E. Michael, D. Baker “Computational Design of an Enzyme Catalyst for a Stereoselective Bimolecular Diels-Alder Reaction”, Science, 2010, 239, 309-313
Read the Science paper
Read the article in The Seattle Times
Read the Chemistry World article
Also visit faculty webpages for Michael Gelb, Forrest Michael and David Baker.