Angew. Chem. Int. Ed. 51, 5431–5434 (2012)

Using an external stimulus to switch on and off the function of biomolecules such as enzymes is useful both in biomedical research and in the development of new therapies. The use of light as the stimulus is particularly attractive because it can be applied rapidly and in a spatially and temporally controlled manner. Modifying large, complex molecules such as enzymes can be difficult, and some researchers have moved towards producing light-regulated enzyme inhibitors.

Now, Danielle Wilson and Neil Branda from Simon Fraser University in Canada have developed an approach that involves preparing a photochemically controlled cofactor mimic. Some enzymatic cofactors are small organic molecules that are more easily amenable to the necessary modifications to make them responsive to a photostimulus. In addition, the same cofactor can be involved in many different enzymatic processes. This approach thus has the potential to be much more widely applicable.

Vitamin B6 (pyridoxal 5′ phosphate) is the cofactor that Wilson and Branda have chosen to mimic; it is involved in a range of enzymatic reactions and is also known to act as a catalyst alone. The key feature of the displayed activity is the through-bond electronic connection of an electron-withdrawing pyridinium with an aldehyde. In one example of its activity, the aldehyde forms a Schiff base (or imine) with an amino acid.

The electronic connection with the pyridinium enhances the acidity of the amino acid's α-hydrogen and facilitates racemization. To create their mimic, Wilson and Branda prepared a molecule in which the well-known dithienylethene photoswitch separates the aldehyde and the pyridinium.

In the inactive form of the catalyst the aldehyde and pyridinium are 'insulated' from one another. Irradiation with UV light induces a ring-closing electrocyclization that 'connects' the two groups. The ring-closed form of the catalyst was shown to catalyse the racemization of L-alanine. Irradiation with visible light causes ring opening and returns the catalyst to the inactive state, which is a poor catalyst for racemization.