Reverse Enzymology

Reverse Enzymology is a new idea for studying and improving small molecule catalysts - catalysts that are important in industry.  There are literally hundreds of these, many of which are essential for the synthesis of drugs or used in energy production, and most of them were derived empirically.  Little is known about their mechanism of action, and consequently there are no systematic approaches possible for their improvement.  They frequently cannot be crystallized and thus even their active conformations are often unknown.  

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(click to enlarge image)

Our idea is to take advantage of the techniques developed over the past 25 years for studying enzyme catalytic mechanisms crystallographically.  We and others have worked out ways of trapping complexes with substrates, stabilizing intermediates, and determining detailed reaction mechanisms of pretty much any enzyme that can be crystallized (see the "Time-Resolved Crystallography" page of this website for details). We propose to exploit this technology for the study of small molecule catalysts by binding them to a readily cystallizable protein, and then introducing substrates into the crystal containing the catalyst-bound protein under conditions that allow us to observe substrate-catalyst complexes, including intermediates, at atomic resolution.  We have two host proteins now in the lab, one for water-soluble catalysts and one for more hydrophobic catalysts.  Both readily form crystals that diffract to almost 1 Angstrom resolution.  We have devised what we hope may be general schemes for coupling a wide range of catalysts to them, covalently in some cases but also non-covalently.  We have initiated collaborations with some organic and organometallic chemists who are in the business of discovering new catalysts for organic synthesis and energy production, and who have important catalysts whose mechanisms are not understood.

We envision this new approach - which we call Reverse Enzymology because it reverses the conventional paradigm of using insights and techniques from small molecule chemistry to help explain how enzymes work; see Figure - as a completely new way of studying and improving catalysts.  It leverages other work we have done and are continuing to do on enzyme reaction mechanisms in a novel way, by using protein crystals and large-molecule crystallographic techniques as tools for fundamental studies of small molecule reactions that are not amenable to the conventional approaches of organic and organometallic chemistry.  It's a new field, we hope.