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Biological Chemistry

Evolved enzymes serve up diverse cyclopropanes

Heme proteins make all possible isomers of prized 3-membered rings

by Carmen Drahl
March 1, 2018 | A version of this story appeared in Volume 96, Issue 10

Each engineered heme protein (colored ribbons) catalyzes formation of a different cyclopropane stereoisomer.
Reaction scheme demonstrating transformation of an unactivated alkene into cyclopropanes. Four different heme proteins catalyze the reaction, each generating a different stereoisomer.
Each engineered heme protein (colored ribbons) catalyzes formation of a different cyclopropane stereoisomer.

With some engineering in the lab, a quartet of iron-containing heme proteins from microbes can convert inert alkenes into each possible stereoisomer of cyclopropanes, which are valuable motifs in medicinally active compounds (ACS Cent. Sci. 2018, DOI: 10.1021/acscentsci.7b00548). Previous engineered proteins needed help from an artificial cofactor to complete this feat. This work suggests that heme proteins are perfectly capable of doing this chemistry on their own.

Building cyclopropanes with protein catalysts is not new, says Frances H. Arnold, the California Institute of Technology professor who led the work. However, prior heme protein catalysts made by her group and others worked best on relatively reactive alkenes. “These proteins are being commercialized, and our clients want more challenging cyclopropanations,” including transformations of unactivated alkenes, she says.

So graduate student Anders M. Knight and colleagues used directed evolution, which simulates natural selection, to find promising candidates. They optimized four heme-containing proteins from bacteria and archaea, each of which produced a different cyclopropane stereoisomer from the unactivated alkene 1-octene.

The cyclopropane-making reaction, a carbene transfer, takes place inside Escherichia coli cells and works in the presence of alcohols and other groups that might normally interfere with the reaction. Caltech has filed a provisional patent application on the technology.

“This work shows that the diversity of heme proteins in nature, coupled with the power of directed evolution, can be a route to novel stereoselective catalysts,” says John Hartwig of the University of California, Berkeley. His team has carried out this chemistry using proteins with a nonnatural iridium cofactor. So far, the new heme proteins convert terminal alkenes only, but Hartwig thinks with more work, they could convert internal alkenes too.

Knight agrees. “These active sites are very tunable,” he says. Arnold adds, “I hope that as we do more difficult target substrates, it’ll push people in industry to give this a try.”



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