My research focusses on enzymes that sense and signal for stress, predominantly in plants. We investigate the structural and functional features of these enzymes that allow them to perform their functions, then try to find ways to manipulate their activity to improve stress tolerance. We work closely with biologists to enable us to implement our findings into cells and organisms.
Plant Cysteine Oxidases
Much of our focus is on the Plant Cysteine Oxidases, which are oxygen-sensing thiol dioxygenases that are important in molecular responses to flooding. They catalyse the oxidation of Cysteine at the N-termini of target proteins to Cys-sulfinic acid, triggering the degradation of these proteins via the N-degron pathway. Key substrates of the Plant Cysteine Oxidases are transcription factors which drive adaptive responses to the low oxygen experienced upon flooding. The oxygen-sensing properties of the Plant Cysteine Oxidase therefore connect the availability of oxygen with the physiological adaptations submergence. Our kinetic analyses identified that the Plant Cysteine Oxidases can act as plant oxygen sensors, and our structural studies of these enzymes have revealed important catalytic features at their active sites. Using our mechanistic, kinetic and structural knowledge of these enzymes, we are finding ways to manipulate Plant Cysteine Oxidase activity to improve submergence tolerance whilst still maintaining a healthy and productive plant.
Redox Stress in Plants
Elevated reactive oxygen species (ROS) arises as a result of a number of stresses in plants, including low oxygen. Since the sulfhydryl groups on cysteine side chains are particularly susceptible to oxidation, abiotic stress could therefore trigger oxygen-sensing signalling pathways in a non-enzymatic manner. ROS and other redox stress-related species can also have a wider range of impacts on plant cells, ranging from stress-signalling to non-specific cellular damage. We are interested in understanding how ROS and other redox-active molecules impact on plant cells, in particular on low oxygen signalling events. This includes collaborating with colleagues in the Dept. Chemistry to use redox-sensing probes to quantify redox markers in plant cells.
Thiol Dioxygenases in Humans
In collaboration with colleagues from the University of Pisa and the Nuffield Department of Medicine in Oxford, we identified that a thiol dioxygenase in humans (Cysteamine Dioxygenase) is homologous to the Plant Cysteine Oxidases in that it regulates the stability of certain proteins with N-terminal cysteine residues in an oxygen-dependent manner, meaning it is a novel oxygen sensor in humans. We are now investigating the role of ADO in more detail to understand the role it plays in hypoxic disease states.