In mitochondria, eubacteria and chloroplasts, the synthesis of ATP is made by a complex molecular machine known as ATP synthase. We want to understand how this machine works, and to use that knowledge for medical benefit. We work mainly on the enzyme from mitochondria, and increasingly on the enzymes from eubacteria. The bacterial and closely related chloroplast enzymes have many common features with the enzyme from mitochondria. The mitochondrial ATP synthase is found in the inner membranes of the organelle, where it uses the transmembrane proton motive force (pmf) generated by the oxidation of nutrients as a source of energy for making ATP. The pmf is coupled to the chemical synthesis of ATP from ADP and phosphate by a rotary mechanism illustrated in the animation below. During ATP synthesis, the central rotor turns in the direction shown about 150 times every second. In order to provide energy to sustain our lives, every day, each one of us produces a quantity of ATP by this mechanism that is approximately equal to our body weight.
Although the structure and the mechanism of the enzyme now appear in standard text-books, key molecular details, required for a full understanding of its mechanism, are lacking. Also, there are significant and largely unexplored differences between the structures of the human and bacterial enzymes and how their activities are regulated. We wish to define these differences in structures and regulation between human and bacterial enzymes so as to develop the ATP synthase as a target for developing new antibiotics to combat multiple drug resistant organisms. It is already an established clinical target for treating tuberculosis.
The activities of the group are focussed on three main areas:
- The structure and function of ATP synthases
- The biogenesis and assembly of the human ATP synthase
- The possible involvement of the human enzyme in cell-death via the permeability transition in mitochondria