Transition state analysis

If we want to understand how enzymes work and how to inhibit them, we need to understand how they stabilize their transition states (TSs). (Learn more about transition states here).

Enzymes catalyze reactions by binding TSs more tightly than anything else - up to 10²⁰-fold tighter than substrates or products. TS mimics - stable molecules that mimic the shape and charge distribution of the TS - are extremely potent inhibitors. Developing new TS mimics requires a deep understanding of catalysis and the TS structure. The challenge in studying TSs is that they exist for ~50 fs, and their concentration is effectively zero.

The only way to experimentally determine TS structures is measuring kinetic isotope effects (KIEs). (Learn about KIEs here).

Only a handful of labs in the world are able to perform TS analysis using KIEs.

Published TS analyses

We have determined the TS structures for:

Current research

We are currently performing TS analyses on the α-carboxyketose synthases (αCKSs). As part of our quest to create new αCKSs inhibitors, we are determining their TS structures. The αCKSs have been the targets of inhibitor design since the 1970s, but after > 40 years of effort, potent inhibitors remain rare. One of the major challenges is that the detailed catalytic mechanism is not understood. This is a serious limitation to inhibitor design since no one knows exactly which TS structure they should be trying to mimic. We are developing new methods to determined the TS structures of αCKSs.

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