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
• Director of the NIEHS Center and Interim Director of the Sealy Center for Environmental Health and Medicine
• Mary Gibbs Jones Distinguished Chair in Environmental Toxicology

Dr. Halpert earned his B.A. in Scandinavian Languages from the University of California at Los Angeles in 1971, his PhD. in Biochemistry from Uppsala University, Sweden in 1977, and his M.S. in Toxicology from 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. He served as Editor for Drug Metabolism and Disposition from 2000-2005. Dr. Halpert has trained 13 predoctoral students and 24 postdoctoral fellows.

Dr. Halpert's research for the past 30 years has focused on 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 likely contributes to individual susceptibility to environmental toxicants as well. 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. P450 2B enzymes were among the first mammalian cytochromes P450 to be purified and cloned and 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 in that conformational changes resulting from ligand binding and/or protein-protein interactions play a key role in substrate binding and turnover.

Selected Publications:

Zhao, Y., White, M.A., Muralidhara, B.K., Sun, L., Halpert, J.R., and Stout, C.D. Structure of microsomal cytochrome P450 2B4 complexed with the antifungal drug bifonazole: Insight into P450 conformational plasticity and membrane interaction. J. Biol. Chem. 281:5973-5981 (2006).

Muralidhara, B.K., Negi, S., Chin, C.C., Braun, W., and Halpert, J.R. Conformational flexibility of mammalian cytochrome P450 2B4 in binding imidazole inhibitors of different ring chemistry and side chains: Solution thermodynamics and molecular modeling. J. Biol. Chem. 281:8051-8061 (2006).

Tsalkova, T., Davydova, N.Y., Halpert, J.R., and Davydov, D.R. Mechanism of interactions of a-naphthoflavone with cytochrome P450 3A4 explored with an engineered enzyme bearing a fluorescent probe. Biochemistry 46:106-119 (2007).

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

Davydov, D.R., Baas, B.J., Sligar, S.G., and Halpert, J.R. 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 (2007).

List of Publications in Pub Med