Enzymes serve up diverse cyclopropanes

Abstract

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