Issue Date: February 28, 2011
Big Enzyme Takes On Tiny Target
Chemists in Germany have discovered a way to persuade a cytochrome P450 (CYP), an enzyme that normally oxidizes large molecules such as fatty acids, steroids, and terpenoids, to do its work on the tiniest of alkanes, methane. The team, led by Manfred T. Reetz at the Max Planck Institute for Coal Research, in Mülheim, Germany, induced CYP to work on the exceptionally small target by introducing a chemical “guest” into the active site to fill the unused space (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201006587).
Methane is at least an order of magnitude smaller than CYP’s usual substrates, and it doesn’t have a high probability of orienting properly for oxidation to occur at CYP’s catalytic heme active site. To fill the unwanted space, Reetz’s team used a perfluorocarboxylic acid, which also helps push the reaction forward by partly converting the catalytic iron species in the active site from low spin to the catalytically active high spin.
The work provides “a novel, readily applicable handle by which to tune the reactivity and selectivity of both natural and engineered enzymes,” says M. Christina White, a chemist at the University of Illinois, Urbana-Champaign.
The work also offers new inspiration for turning methane into methanol, an attractive alternative to oil or natural gas feedstocks for making fuels and organic chemicals. Turning methane into methanol can be tricky because methane has the strongest C–H bond of any alkane. Reetz’s team “has shown for the first time that heme iron enzymes can generate an oxidant capable of oxidizing methane. These findings are certain to influence future efforts to develop practical enzymatic systems for industrial processes” to turn methane into methanol, White says.
Reetz aims to adjust the active sites of other enzymes so they can accommodate other reactants. He plans to use the “guest” strategy in combination with directed evolution to enable enzymes to transform nonnative substrates.
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