Feeling inhibited?

Researchers in Cambridge, UK, have turned their hand towards the tricky problem of understanding the mechanism of action of thiamin diphosphate dependent enzymes.

These enzymes use thiamin diphosphate as a coenzyme during the process of making and breaking carbon-carbon bonds. By making two coenzyme mimics, 3-deazathiamin diphosphate and a simpler analogue with a benzene ring instead of a thiazolium ring, Finian Leeper and colleagues from the University Chemical Laboratory hope to be able to obtain crystal structures of the enzyme-coenzyme mimic. Detailed study will then allow the binding mode to be understood better.

Both compounds show powerful inhibition properties, binding to pyruvate decarboxylase much faster than the coenzyme and up to 25 000 times more tightly. In the case of pyruvate decarboxylase, Leeper describes the binding to 3-deazathiamin diphosphate to be so tight as to be ’essentially irreversible even though no covalent linkage is formed’.

Furthermore, because their two mimics can be easily modified Leeper plans to make further models of proposed intermediates along the mechanistic pathway and then elucidate their detailed crystal structures.

Steven Evans