Dr. James R. Halpert: Drug Metabolism

Research Summary: Drug Metabolizing Enzymes

Dr. Halpert's research focuses 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 environmental toxicants. Currently there is great interest in developing approaches for predicting P450-mediated metabolism of new compounds. Progress in this area is dependent on sophisticated understanding of the structural determinants and mechanisms of enzyme function.

Dr. Halpert's group utilizes X-ray crystallography in conjunction with a variety of solution biophysical approaches to probe the role of conformational changes in mammalian P450 function. Recent structures of rabbit P450 2B4 and human P450 2B6 have provided compelling evidence that the enzymes work by an induced-fit mechanism. This has important implications for using static X-ray crystal structures to predict P450-mediated substrate oxidation. Related studies on P450 3A4, the major human drug metabolizing enzyme, employ pressure-perturbation spectroscopy, fluorescence resonance energy transfer, absorbance spectroscopy, and rapid kinetics to understand the allosteric behavior of this enzyme. Recent findings demonstrate that conformational changes resulting from ligand binding and/or protein-protein interactions play a key role in substrate binding and turnover.

Academic Achievements

Education: B.A. in Scandinavian Languages (1971) UCLA; M.S. in Toxicology (1978) Karolinska Institute, Sweden; Ph.D. in Biochemistry (1977) Uppsala University, Sweden.

Awards and Honors: Faculty Development Award in Pharmacology (1984); NIH Research Career Development Award (1985); NIH Merit Award (2005); Mary Gibbs Jones Distinguished Chair in Environmental Toxicology (2004); Fellow, American Association for the Advancement of Science (2006); Editor Drug Metabolism Disposition (2000-2006); Bernard B. Brodie Award in Drug Metabolism (2010).

Leadership Experience: Chairman, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX (1998-2008); Director, Environmental Health Sciences Center,UTMB (2003-2008); President-Elect, American Society for Pharmacology and Experimental Therapeutics (2009-present).

Teaching

• Pharmacy: Contemporary Topics in Pharmacology (SSPPS 218A, B).
• Pharmacogenomics (SSPPS 219).
• Pharmaceutical Biochemistry (SSPPS 223).
• Principles of Pharmacology (SOM 217A).

Key Contributions to Pharmaceutical Sciences

• Pioneered use of selective inhibitors to probe cytochrome P450 function.
• Elucidated active sites of P450 2B and 3A enzymes by site-directed mutagenesis and homology modeling.
• Solved multiple mammalian P450 X-ray crystal structures and demonstrated major conformational changes upon ligand binding.
• Elucidated role of conformational flexibility and heterogeneity in allostery of human P450 3A4.

Selected Recent Publications (from 167 peer-reviewed articles)

Oezguen et al. (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 et al. (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 et al. (2009). Crystal structures of cytochrome P450 2B4 in complex with the inhibitor 1-biphenyl-4-methyl-1H-imidazole: ligand induced structural response through α-helical repositioning. Biochemistry 48:4762-4771.

Gay et al. (2010). Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl)imidazole at 2.0Å resolution. Mol. Pharmacol. 77:529-538.

Potential Collaborative Programs with the Pharmaceutical Industry

• Thirty years of expertise in drug metabolizing enzymes- Diverse array of laboratory approaches including structural biology, solution biophysics, and biochemical characterization of P450 enzymes.