Discovery unlocks secrets of how nature synthesizes important chemicals

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The groups of Professors Yi Tang and Ken Houk and Japanese scientists have discovered a new mode of enzyme catalysis recently reported in the journal Nature.

Tang and Houk, in the departments of Chemistry and Biochemistry, and Chemical and Biomolecular Engineering, at UCLA have teamed with scientists in the Kenji Watanabe group at the University of Shizuoka in Japan to determine how nature produces a complex natural product leporin C that has insecticidal activities. Enzymes are Nature’s protein catalysts, and they often utilize small molecules, known as cofactors, to facilitate reactions. The new enzyme uses a cofactor known as SAM in an unprecedented way to stabilize the transition state.

Painstaking isolation and biochemical characterization by Dr. Masao Ohashi from the Tang group identified the new enzyme and showed it catalyze several reactions never before observed in nature. Computational modeling by postdoc Dr. Fang Liu of the Houk group led to the discovery that these reactions happen in an unusual way where two pericyclic reactions, which are among the most powerful tools to make carbon-carbon bonds, are catalyzed.  A sketch of unusual transition state that gives two products, and the potential energy computed for the reactions, are shown below.


Despite their prominence in total synthesis, only three naturally existing enzymatic pericyclic reactions were known before the work of the UCLA team.  The catalysis involves the ambimodal transition state, a term coined by Houk, shown in the diagram above, to form two products.

Ohashi’s work showed the enzyme is an unprecedented S-adenosyl-L-methionine dependent (SAM) protein LepI that can catalyze dehydration, competitive IMDA/hetero-DA (HDA) reactions via the ambimodal transition state, and a retro-Claisen rearrangement leading to the formation of the dihydropyran core of the fungal natural product leporin. The molecule SAM is commonly involved in several different enzyme reactions, but serves a completely unprecedented role in facilitating the reactions studied here. LepI is the first example of an enzyme catalyzing a (SAM-dependent) retro-Claisen rearrangement.

This work shows that many pericyclic biosynthetic enzymatic transformations are yet to be discovered in the intriguing enzyme toolboxes of Nature.  

From UCLA Newsroom (by Matthew Chin):

UCLA, Japanese scientists discover new way to speed up chemical reactions

Enzyme-powered catalysis could be powerful new tool to synthesize chemicals

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The study, led by UCLA’s Kendall Houk (left) and Yi Tang, suggests that there could be many other naturally occurring enzymes that could be synthesized in similar ways. Reed Hutchinson/UCLA (Houk); UCLA (Tang)

A team of scientists and engineers from UCLA and Japan’s University of Shizuoka has discovered a new mode of enzyme catalysis, the process that speeds up chemical reactions.

The researchers also demonstrated that the enzyme, called LepI, can catalyze reactions that were not previously observed in nature. Through computational modeling, they found that the process happens in a unique way that can create two different molecules at once.

“Mother Nature has amazing powers as a chemist in using enzymes to construct complex molecules in very efficient ways,” said Yi Tang, a UCLA professor of chemical and biomolecular engineering and a principal investigator on the study. “Our discovery showcased one naturally occurring enzyme and how it can be used as a tool to catalyze a very important and heavily studied synthetic reaction. This also suggests there could many more such enzymes waiting to be discovered and engineered.”

The study was published in the journal Nature. In addition to Tang, the research was led by Kendall Houk, who holds UCLA’s Saul Winstein Chair in Organic Chemistry, and Kenji Watanabe, a professor of pharmaceutical sciences at Shizuoka.


Enzymes are proteins that play a critical role in catalysis — the process of facilitating chemical reactions. (They help yeast break down starch into sugars, for example.) And enzymes use smaller molecules known as cofactors to help get those reactions going. 

Image right: Three pericyclic reactions initiated by LepI, with leporin C (bottom left) as the end product. UCLA and Nature 

The new mode of catalysis became apparent as the researchers were studying a substance called leporin C, which is naturally produced by fungi and has insecticidal properties. The scientists discovered that an enzyme cofactor called S-adenosyl-L-methionine dependent, or SAM, helps LepI start a chemical reaction that ultimately produces leporin C.

The research revealed that LepI uses SAM in a unique way to stabilize molecules involved in a multiple-step chemical reaction, and that three pericyclic reactions take place during that process. Pericyclic reactions, so-called because they form or break chemical bonds on a ring (or “cycle”) of atoms, are among the most powerful tools for forming carbon-to-carbon bonds.

Among the UCLA researchers who made key contributions to the research were postdoctoral scholar Masao Ohashi, who isolated and characterized the enzyme, and showed that it catalyzed several reactions that had been observed before in nature; postdoctoral scholar Fang Liu, who performed computational modeling showing the unusual way the reactions happen; and Zhongyue Yang, a doctoral student, who used molecular dynamics simulations to determine what factors controlled the formation of specific chemical products. The paper’s other authors were Yang Hai, Mengbin Chen, Man-cheng Tang, all members of Tang’s research group at UCLA; and Michio Sato of Shizuoka.

Houk also holds a UCLA faculty appointment in chemical and biomolecular engineering. Tang holds UCLA faculty appointments in chemistry and biochemistry, and in bioengineering. The research was supported by the National Institutes of Health, the National Science Foundation and the Japan Society for the Promotion of Science.

Other authors on the paper include Yang Hai, Mengbin Chen, Man-cheng Tang, and Michio Sato.

Houk also holds a faculty appointment at UCLA in chemical and biomolecular engineering. Tang holds faculty appointments at UCLA in chemistry and biochemistry, and bioengineering.

The research was supported by the National Institutes of Health, the National Science Foundation and the Japan Society for the Promotion of Science.