The Skaggs School of Pharmacy & Pharmaceutical Sciences

James R. Halpert

Dr. James Halpert joined the Skaggs School of Pharmacy and Pharmaceutical Sciences in March, 2008 as Professor and Associate Dean for Scientific Affairs. Before coming to UCSD, Dr. Halpert was at the University of Texas Medical Branch where he served as Professor and Chairman of the Department of Pharmacology and Toxicology and Director of the NIEHS Center.

Dr. Halpert earned his B.A. in Scandinavian Languages from the University of California at Los Angeles in 1971, his Ph.D. in Biochemistry from Uppsala University, Sweden in 1977, and his M.S. in Toxicology from the Karolinska Institute, Stockholm, Sweden in 1978. He was a member of the NIH Pharmacology Study Section from 1992-1995 and served as Chairman from 1993-1995. Dr. Halpert served as Editor for Drug Metabolism and Disposition from 2000-2005. Starting July 1, 2009 he will be President-Elect of the American Society for Pharmacology and Experimental Therapeutics. Dr. Halpert has trained 13 predoctoral students and 28 postdoctoral fellows.

Dr. Halpert's research for the past 30 years has involved the structure and function of cytochromes P450. Heterogeneity in the expression levels and/or activities of these important drug-metabolizing enzymes is a major determinant of individual response to medications and environmental toxicants. Because many of the failures in investigational drug development result from suboptimal pharmacokinetics, drug interactions, and/or toxicity, methods for predicting cytochrome P450-mediated metabolism of new compounds are currently in great demand. Progress in this area is dependent on sophisticated understanding of the structural determinants and mechanisms of cytochrome P450 function.

Dr. Halpert's group has focused on cytochromes P450 of the 2B and 3A subfamilies. For decades P450 2B enzymes have served as a prototype for biochemical, biophysical, and structure-function studies. The recent X-ray crystal structures of P450 2B4 have provided compelling evidence that this enzyme works by an induced-fit mechanism, which has important implications for using static X-ray crystal structures to predict P450-mediated substrate oxidation. The combination of X-ray crystallography, solution biophysics, and virtual screening promises to be a very powerful approach for predicting P450 ligands. Dr. Halpert's current work on the P450 3A subfamily is devoted to determining the mechanistic basis for the atypical kinetics of substrate oxidation by human P450 3A4. This enzyme is of particular pharmacological and toxicological significance due to its abundance in adult human liver and intestine and its ability to metabolize a vast array of therapeutic and environmental agents of diverse structures, sizes, and shapes. Through the use of a variety of solution biophysical approaches including pressure-perturbation spectroscopy, fluorescence resonance energy transfer, and absorbance spectroscopy, Dr. Halpert and colleagues have provided compelling evidence that P450 3A4 has many of the hallmarks of a classical allosteric enzyme. Thus, conformational changes resulting from ligand binding and/or protein-protein interactions play a key role in substrate binding and turnover.

Selected Publications:

Muralidhara, B.K., Negi, S.S., and Halpert, J.R. (2007). Dissecting the thermodynamics and cooperativity of ligand binding in cytochrome P450eryF. J. Am. Chem. Soc. 129:2015-2024.

Davydov, D.R., Baas, B.J., Sligar, S.G., and Halpert, J.R. (2007). Allosteric mechanisms in cytochrome P450 3A4 studied by high-pressure spectroscopy: pivotal role of substrate-induced changes in the accessibility and degree of hydration of the heme pocket. Biochemistry 46:7852-7864.

Kumar, S., Zhao, Y., Sun, L., Halpert, J.R., and Muralidhara, B.K. (2007). Rational engineering of human cytochrome P450 2B6 for enhanced expression and stability: Importance of a Leu264Phe substitution. Mol. Pharmacol. 72:1191-1199.

Muralidhara, B.K., Sun, L., Negi, S., and Halpert, J.R. (2008). Thermodynamic fidelity of the mammalian cytochrome P450 2B4 active site in binding substrates and inhibitors. J. Mol. Biol. 377:232-245.

Oezguen, N., Kumar, S., Hindupur, A., Braun, W., Muralidhara, B.K., and Halpert, J.R. (2008). Identification and analysis of conserved sequence motifs in cytochrome P450 family 2: Functional and structural role of a motif 187RFDYKD192 in CYP2B enzymes. J. Biol. Chem. 283: 21808-21816.

Davydov, D.R., Davydova, N.Y., and Halpert, J.R. (2008). Allosteric transitions in cytochrome P450eryF explored with pressure-perturbation spectroscopy, lifetime FRET, and a novel fluorescent substrate, Fluorol-7GA. Biochemistry 47:11348-11359.

Gay, S.C., Sun, L., Maekawa, K., Halpert, J.R., and Stout, C.D. (2009). Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole: ligand induced structural response through -helical respositioning. Biochemistry [Epub ahead of print, April 27].

List of Publications in Pub Med