Enzyme coordinates pericyclic reaction trifecta

Pericyclic reactions, in which electrons move in concert to rearrange a molecule’s structure, are standard tools for synthetic chemists. But examples of such transformations in nature are fairly rare. Chemists have now identified an enzyme that catalyzes three pericyclic reactions in the biochemical pathway that produces the fungal natural product leporin C.

“This really opens up the idea that nature is able to affect reactions of much broader generality than we ever knew before,” says Kendall N. Houk, a University of California, Los Angeles, chemistry professor who led the study along with UCLA’s Yi Tang and University of Shizuoka’s Kenji Watanabe.

The enzyme, called LepI, begins by dehydrating a leporin precursor to generate a reactive intermediate. This intermediate, with the help of LepI, can either undergo a hetero-Diels-Alder reaction to produce the desired compound leporin C, or it can perform an intramolecular Diels-Alder reaction to produce a different intermediate that then is subject to a retro-Claisen rearrangement to produce leporin C (Nature 2017, DOI: 10.1038/nature23882).

When used by synthetic chemists, these pericyclic transformations often have to be performed at high temperatures, Tang notes. Also, he points out, it can be difficult to control the products’ regio- and stereochemistry. “As with any biocatalyst, this enzyme has potential to be engineered to catalyze such reactions under mild conditions with selective product formation,” Tang says. He also points out that leporins are deadly to insects, so this enzyme’s chemistry could lead to selective and potent insecticides either via synthesis of novel leporin analogs or large-scale bioengineered production of native leporins.

LepI is also noteworthy because the enzyme uses S-adenosyl-L-methionine (SAM) in an unexpected manner. SAM generally transfers methyl groups to substrates. But based on computational work, the chemists speculate that in LepI, SAM’s methyl group, which is adjacent to a positively charged sulfur, is acting as a hydrogen-bond donor to catalyze the pericyclic transformations.

“This places LepI on a short but growing list of methyltransferase homologs that catalyze unusual transformations of the carbon skeletons in their substrates rather than conventional methylation reactions,” comments Hung-wen (Ben) Liu, an expert in enzyme mechanisms at the University of Texas, Austin.

The chemists are currently using crystallographic techniques to try to find definitive experimental evidence for what SAM does in LepI.