Chancellor's Professor,
Associate Chairman,
Director of Center for Structural Biology

Department of Biochemistry and Molecular Biology
Indiana University School of Medicine
John D. Van Nuys Medical Science Building
635 Barnhill Drive, Room 4019
Indianapolis, Indiana 46202-5126

Phone: (317) 278-2008
Facsimile: (317) 274-4686
E-mail: thurley@iupui.edu

B.S. in Biochemistry, 1983, Pennsylvania State University, University Park, PA
M.S. in Biochemistry, 1985, Creighton University, Omaha, NE
Ph. D. in Biochemistry, 1990, Indiana University School of Medicine, Indianapolis, IN
Post-doctoral Fellow, 1990-1992, Indiana University School of Medicine, Indianapolis, IN and The Johns Hopkins University School of Medicine, Baltimore, MD

Area of Study

X-ray crystallography of enzymes; probing enzyme function through mutagenesis and small molecule discovery; kinetic analysis of enzyme - ligand interactions.  More details...

Selected Recent Publications

Bateman, R.L., Ashworth, J., Witte, J.F., Baker, L.J., Bhanumoorthy, P., Timm, D.E., Hurley, T.D., Grompe, M. and McClard, R.W. (2007) Slow-onset inhibition of fumurylacetoacetate hydrolase by phosphinate mimics of the tetrahedral catalytic intermediate: Kinetics, crystal structure and pharmacokinetics. Biochem. J. 402:251-260.

Florang, V.R., Rees, J.N., Brogden, N.K., Anderson, D.G., Hurley, T.D. and Doorn, J.A. (2007) Inhibition of the oxidative metabolism of 3,4-dihidyroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal. Neurotox. 28:76-82.

Larson, H., Zhou, J., Chen, Z., Stamler, J.S., Weiner, H. and Hurley, T.D. (2007) Structural and Functional Consequences of Coenzyme Binding to the Inactive Asian Variant of Mitochondrial Aldehyde Dehydrogenase: Roles of Residues 475 and 487. J. Biol. Chem. 282:12940-12950.

Janecki, D.J., Bemis, K.G., Tegeler, T.J., Sanghani, P.C., Zhai, L., Hurley, T.D., Bosron, W.F. and Wang, M. (2007) A Multiple Reaction Monitoring Method for Absolute Quantification of the Human Liver Alcohol Dehydrogenase ADH1C1 Isoenzyme. Anal. Biochem. 369:18-26.

Hurley, T.D., Yang, J., Zhang, L., Goodwin, K.D., Zou, Q., Cortese, M., Dunker, A.K. and DePaoli-Roach, A.A. (2007) Structural Basis for regulation of Protein Phosphatase 1 by Inhibitor-2. J. Biol. Chem. 282:28874-28883.

González-Segura, L., Witte, J.F., McClard, R.W. and Hurley, T.D. (2007) Ternary complex formation and induced asymmetry in orotate phosphoribosyltransferase Biochemistry 46:14075-86.

Chen, C.H., Budas, GR.., Churchill, E.N., Disatnik, M.H., Hurley T.D., Mochly-Rosen, D. (2008) Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart. Science 321:1493-5.

Aneetha H, O'Dell DK, Tan B, Walker JM, Hurley TD. (2009) Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: synthesis of N-acyl glycinals. Bioorg Med Chem Lett. 19(1):237-41. PMID: 19013794

Perez-Miller S, Younus H, Vanam R, Chen CH, Mochly-Rosen D, Hurley TD. (2010) Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant. Nat Struct Mol Biol. 2010 Feb;17(2):159-64. Epub 2010 Jan 10.

Baraibar MA, Muhoberac BB, Garringer HJ, Hurley TD, Vidal R. (2010) Unraveling of the E-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration. J Biol Chem. 2010 Jan 15;285(3):1950-6. Epub 2009 Nov 18.

Perez-Miller, Zou, Q., Novonty, M.V. and Hurley, T.D. (2010) High resolution X-ray structures of mouse major urinary protein nasal isoform in complex with pheromones. Protein Sci. 19:1469-1479.

Baskaran, S., Roach, P.J., DePaoli-Roach, A.A. and Hurley, T.D. (2010) Structural Basis for Glucose-6-Phosphate Activation of Glycogen Synthase. Proc. Nat. Acad. Sci. USA 107:17563-17568.

Allen, E.M.G., Anderson, D.G., Florang, V.R., Khanna, M., Hurley, T.D. and Doorn, J.A. (2010) Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: Implications for the mechanism of enzyme inhibition. Chem. Res. Toxicol. 23:1843-1850.

Tagliabracci, V.S., Heiss, C., Glushka, J., Karthik, C., Contreas, C.J., Ishihara, M., Azadi, P., Hurley, T.D., DePaoli-Roach, A.A., and Roach, P.J. (2011) Phosphate incorporation during glycogen synthesis and Lafora Disease. Cell Metab. 13:274-282

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Research Interests

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, 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.