Houk group research featured in Nature Chemistry

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Ken Houk, postdoc Yike Zou, and collaborators design and improve, by directed evolution, most potent protein catalyst yet known for a Diels-Alder reaction. 

The team’s paper titled “Efficient Lewis Acid Catalysis of an Abiological Reaction in a de novo Protein Scaffold” was published in the February issue of Nature Chemistry.

Professor Ken Houk holds the Saul Winstein Distinguished Research Chair in Organic Chemistry at UCLA. Building on the designs of former Houk postdoc Gonzalo Jiménez-Osés, Houk and Zou have joined with Professor Don Hilvert and his group at the ETH in Zurich to design and improve, by directed evolution, the most potent protein catalyst yet known for a Diels-Alder reaction. This reaction and the designed active site are shown below. There are natural Diels-Alderases that catalyze Diels-Alder reactions with precise control of stereochemistry, but the newly designed one is a much better catalyst. 

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Professor Ken Houk, Dr. Yike Zou, and Dr. Gonzalo Jiménez-Osés (CIC biGUNE)
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A computationally designed artificial enzyme to catalyze an abiological hetero-Diels-Alder reaction.

Computations by Jiménez-Osés, now at the CIC biGUNE in Bilbao, Spain, were used to design a binding site around a Zn++ ion in a Zn binding protein in an evolutionarily naïve, zinc-containing four-alpha-helices bundle protein structure (MID1). The Zn++ acts to bind a reactant and activate it for the reaction. The design had sufficient activity to be evolved to the best Diels-Alderase known so far. DA7 is completely stereoselective and its proficiency is over 10 billion, which is more than any known natural or unnatural Diels-Alderase.

This work is part of an ongoing effort to use computations to design enzyme catalysts for useful reactions, in the pharmaceutical industry and for laboratory synthesis. 

Penny Jennings, UCLA Department of Chemistry & Biochemistry.  For further information, contact Ken Houk, houk@chem.ucla.edu.