Research Group Photo
Drug Metabolism: Mechanisms and Inhibition
Chemical Mechanisms of Cytotoxicity
Design and Synthesis of Proteinase Inhibitors
COBRE Center in Protein Structure and Function
About Bob Hanzlik
• B.A. 1966, Southern Illinois University at Carbondale
• Ph.D. 1970, Stanford University
• NATO Fellow, Cambridge University, 1970-71
Research Interests
Drug metabolism: enzyme mechanisms and inhibition.
A major interest in our research group is in understanding a
fascinating family of enzymes known as the cytochromes P450. Some of these enzymes metabolize drugs and foreign
compounds while others catalyze biosynthetic processes involving steroid hormones and eicosanoids. We investigate
how P450 enzymes hydroxylate their substrates, often in highly specific ways. Carefully designed "probe" molecules
are synthesized and their metabolism is investigated using state-of-the-art analytical methods. Stable- and radioisotope
labeling and kinetic isotope effects are also often employed. (
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Chemical mechanisms of cytotoxicity.
P450 enzymes can also "bioactivate" many simple organic compounds to form
chemically-reactive cytotoxic metabolites. Examples include bromobenzene, thiobenzamide, the analgesic drug acetaminophen,
the herbicide molinate, and the general anesthetic halothane. Biotransformation of these and many other agents by P450
enzymes sometimes generates chemically-reactive metabolites which express their reactivity by reacting with cellular proteins,
ultimately injuring the cell. A major objective of our group is the identification of important target proteins and the
structures of the protein-metabolite adducts formed by a number of simple cytotoxic compounds. Adducted proteins are located
on 2D gels by autoradiography or western blotting and identified, along with their adducts, by modern methods of proteomics
based on MALDI-TOF-MS and HPLC/MS/MS. (
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In addition to the research activities listed above, Dr. Hanzlik is the Principal Investigator and Director
of a multi-campus NIH Center of Biomedical Research Excellence in Protein Structure and Function. (
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information)
Protease inhibitors.
Although this project has ended, we have also worked on the design, synthesis and evaluation of inhibitors for cysteine protease enzymes. Cysteine proteases
play unique biological roles in virus-infected mammalian cells, certain cancer cells, parasitic protozoa, and in processes
leading to programmed cell death (apoptosis). Although their biology is diverse, cysteine proteinases share a common mechanism
of action, and the lack of effective therapeutic agents in these areas creates an opportunity for novel approaches to drug
design. (
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For more information, please contact:
E-mail:
rhanzlik@ku.edu
4048 Malott Hall
Tel: 785-864-3750
