Professor Holyoak's laboratory’s research interests lie in the areas of enzyme structure, mechanism, inhibition and allostery. In light of these general interests our research currently focuses on the role that conformational plasticity plays in these areas of enzymology and how these dynamic aspects of enzyme structure can be exploited in the regulation of enzyme function. We are currently investigating these phenomena in two enzyme families:
1) the GTP-dependent phosphoenolpyruvate carboxykinases and
2) the IgA1 protease family of bacterial proteases
using primarily the tools of steady-state kinetics and x-ray crystallography.
Phoshoenolpyruvate Carboxykinases (PEPCK)
Our investigations of PEPCK utilize these enzymes as a model system in which to investigate and develop our understanding of the linkage between the conformational plasticity of protein structure and enzyme function and molecular recognition. However, our studies on PEPCK should have additional impacts upon human health as PEPCK is an important cataplerotic enzyme whose activity in humans and other mammals is essential to the maintenance of blood glucose levels. As a consequence, flux through PEPCK contributes to the fasting hyperglycaemia observed in individuals afflicted with either Type I or Type II diabetes and has recently been implicated as a potential player in important biological processes such as cancer and aging.
IgA1 proteases
In the IgA1 proteases we are interested in discovering the mechanisms by which this enzyme family, containing both serine and metallo-protease isoforms, selectively cleaves a narrow range of protein substrates, primarily human immunoglobulin A1 (IgA1). In particular we are interested in how conformational flexibility plays a role in substrate selectivity and catalytic function in these enzymes. IgA1 proteases are produced in a number of important human bacterial pathogens, including Haemophilus influenzae andStreptococcus pneumoniae, and the evidence supports a definite role for IgA1 proteases in the pathogenesis of mucosal infection.
