Charles T. Grubmeyer, PhD
Professor, Medical Genetics and Molecular Biochemistry
Professor, Fels Institute for Cancer Research and Molecular Biology
- Contact Information
- About Me
The laboratory of Charles Grubmeyer studies the structure and function of the enzyme of nucleotide synthesis, particularly the phosphoribosyltransferases (PRTases). The PRTases make nucleoside monophosphates from the cognate nucleobase and the ribose 5-phosphate donor PRPP. Hypoxanthine-guanine PRTases from humans, Tritrichomonas, Plasmodium falciparum and Bacilli are all under active study, together with bacterial quinolinate, nicotinate and orotate PRTases.
X-ray structures solved with collaborating labs show that PRTases exist in open and closed forms. The open forms are compatible with substrate binding and product release, but are not catalytically competent. The closed forms carry out rapid chemical catalysis but then need to open to release products. The linkage between protein movement and enzyme chemistry is a vital topic in contemporary enzymology, and orotate PRTase provides an excellent model system. With collaborator Mark Girvin of Albert Einstein College of Medicine, we use NMR approaches to study the linkage of movement and chemical catalysis. The NMR allows us to follow protein movement, movement of ligands, and their association and dissociation.
The Grubmeyer laboratory utilizes presteady state kinetics to follow events in catalysis. We have Update and Kintek instruments to permit both stopped flow and chemical quench technologies to be employed. When coupled with NMR measurements, the result is a kinetic picture containing both movement and chemical events. We manipulate the system using mutagenesis to disrupt the roles of vital amino acid residues, and alter the movement/chemistry linkage. What is emerging is an apparently tight linkage between movement and chemistry in orotate PRTase, whose disruption allows for generation of dead-end paths for protein movement.
- Education, Training & Credentials
- University of Alberta, Canada