Collaboration led by Professor Ken Houk may lead to new ways to use enzymes

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A team led by Ken Houk has discovered a naturally occurring reaction in enzymes which could lead to new biological activities and pharmaceutical applications.

Houk’s collaboration with two former group members and researchers at Nanjing University led to the documentation of the first enzymes proven to catalyze [6+4] cycloadditions.

The ability of nature to make 10-membered rings by [6+4] reactions shows that a novel type of natural product architecture is feasible.

The team’s study, “Enzyme-Catalysed [6+4] Cycloadditions in the Biosynthesis of Natural Products,” was published online in the prestigious journal Nature March 13, 2019. 

Houk’s Ph.D. dissertation from some time ago involved the discovery of the first chemical examples of [6+4] cycloadditions. This new work establishes, for the first time, that this reaction has already been happening naturally in enzymes for eons! The enzymes, StmD, NgnD, and others, provide new examples of pericyclases, a type of enzyme that accelerates a pericyclic (in this case, 10-electron cycloaddition) reaction to generate a new ten-membered ring.  StmD is involved in the biosynthesis of streptoseomycin.

Liang%2C%20YongLiu%2C%20FangThe work was carried out in collaboration with two former Houk group members, former UCLA postdoc (left) Yong Liang, now Professor at Nanjing University, and (right) Fang (Acia) Liu (Ph.D. ’14 Chemistry), now Professor at Nanjing Agricultural University, and the groups led by Professors Hui Ming Ge and Ren Xiang Tan at Nanjing University.  These latter groups identified and characterized the enzyme, while Houk, Liang, and Liu carried out quantum mechanics and molecular dynamics calculations to establish the mechanism of this enzyme-catalyzed [6+4] cycloaddition reaction.

Houk, UCLA’s Saul Winstein Professor of Organic Chemistry, has pioneered the use of computer calculations and simulations to study organic chemistry and to predict chemical reactivity that will have important applications in industry and in therapies for fighting disease. To learn more about Houk’s research, visit his group’s website.

Penny Jennings, UCLA Department of Chemistry & Biochemistry,