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Thomas D. Hurley, PhD
Associate Dean for Graduate Education
Dr. Hurley received his PhD in Biochemistry from Indiana University in 1990 under the direction of Dr. William Bosron where his research focused on an analysis of structure and function of human alcohol dehydrogenases and how polymorphisms in these enzymes impact their ability to metabolize beverage ethanol. Dr. Hurley received post-doctoral training at the Johns Hopkins School of Medicine under Dr. Mario Amzel in the Biophysics and Biophysical Chemistry Department where he pursued training in the application of X-ray crystallography to understand enzyme structure and function. He joined the faculty within the Department of Biochemistry and Molecular Biology at Indiana University School of Medicine in 1992. His research areas include the application of X-ray crystallography, enzyme kinetics and small molecule drug discovery to enzyme targets that underlie particular disease states. Dr. Hurley has two broad areas of research interest. The first area focuses on the roles that different human aldehyde dehydrogenases play in cancer stem cells (tumor initiating cells) through the discovery and development of isoenzyme specific small molecule inhibitors. This work is in collaboration with investigators at the Northwestern University School of Medicine and with investigators at the University of Michigan. His second area of interest is in developing inhibitors for human glycogen synthase as a potential treatment for glycogen storages diseases where glycogen over-accumulation is the primary cause of disease.
Titles & Appointments
- Interim Chair, Department of Biochemistry & Molecular Biology
- Chancellor's Professor, IUPUI
- Associate Chair, Department of Biochemistry & Molecular Biology
- Professor of Biochemistry & Molecular Biology
The major focus of my research is to understand, at the molecular level, the processes involved in the recognition and binding of molecules that are directed to the active sites of enzymes. In particular, our recent work has challenged us to understand the functional distinction between active site directed inhibitors, as well as activators. The main approaches utilized in our laboratory are X ray crystallography, inhibitor screening, detailed enzyme kinetics and mass spectrometry. A major focus is to correlate the structural and functional characteristics of the mitochondrial form of aldehyde dehydrogenase. Mitochondrial aldehyde dehydrogenase is the major enzyme involved in the oxidation of ethanol-derived acetaldehyde to acetate. Approximately 50% of the Asian population possesses a single amino acid substitution which renders the enzyme inactive in vivo. Genetic studies have correlated the presence of this mutant allele with a lower incidence of alcoholism, a reduced responsiveness to nitroglycerin and increased mortality following myocardial infarction. The goal of our project is to understand the catalytic function of this important alcohol metabolizing enzyme and how manipulation of its activity through the design of small molecule modulators of its activity can affect these outcomes. Other members of the ALDH superfamily are associated with increased chemoresistance in certain forms of cancer and as biomarkers for cancer stem cells. Consequently, we have a broad interest in the discovery and characterization of small molecules targeted to these ALDH isoenzymes.
Our second major research direction is in collaboration with Drs. Peter Roach and Anna Depaoli-Roach, where we are interested in the structural and functional properties of the enzymes involved in glycogen synthesis; glycogenin and glycogen synthase. We determined the three-dimensional structure of the eukaryotic forms of both enzymes. Each enzyme has a distinct three-dimensional structure and recognizes the UDP-glucose substrate in distinct ways. Glycogen synthase undergoes a remarkable conformational change upon binding its allosteric activator, glucose-6-phosphate and we are studying the mechanisms by which phosphorylation and glucose-6-phosphate regulate this conformational change and, hence, enzyme activity. We are also interested in understanding the chemistry by which the glucose residues are transferred from the UDP-glucose substrate molecule to the specific tyrosine residue on glycogenin and to the glycogen acceptor chain by glycogen synthase. We have recently developed a highly sensitive and quantitative assay by which we can help us address these questions for both enzymes.