F. Peter Guengerich, Ph.D.
Professor of Biochemistry
Tadashi Inagami Chair in Biochemistry
Enzymology involved in metabolism of chemicals
Research Keywords: cytochrome P450, enzyme mechanisms, drug metabolism, steroid metabolism, toxicology, chemical carcinogenesis
Research Specialty: Mechanisms and relevance of cytochrome P450 oxidations
Research Description: Cytochrome P450s (P450s) are the major enzymes involved in the metabolism of drugs, steroids, fat-soluble vitamins, fatty acids, pesticides, chemical carcinogens, natural products, and a wide variety of industrial chemicals. The reactions, mainly oxidations, involve the generation of iron-oxygen complexes that are capable of oxidation by hydrogen atom transfer, abstraction of non-bonded electrons, or nucleophilic attack on carbonyls. P450s compete with intracellular binding proteins for many of the substrates, and direct transfers of substrates from binding proteins to P450s have been demonstrated. The mechanisms of P450 reaction, enzyme kinetics, and the interactions with other proteins are important in the development and use of pharmaceuticals as well as in endocrinology.
The Guengerich laboratory has long experience with human P450s, their structures and chemistry, and interactions relevant to catalytic activity.
Some current projects in the laboratory include:
- Understanding the interaction of human P450 enzymes with fatty acid binding proteins, particularly FABP1 in the liver and FABP3 in the heart.
- Defining the roles of Compound I (FeO3+) and Compound 0 (Fe3+O2¯) in the oxidations of electrophilic substrates (e.g., carbonyls).
- Utilizing high-throughput screening approaches to identify better drugs to control androgen production in the treatment of prostate cancer.
- Quantifying individual P450s and accessory proteins—using proteomics—in regions of several human tissues (e.g., adrenal glands, heart).
We utilize very quantitative approaches involving biochemistry and analytical and organic chemistry. Major techniques include UV-visible and fluorescence spectroscopy, mass and NMR spectrometry, organic synthesis, HPLC/UPLC, enzyme kinetics (including steady-state, rapid kinetics, and kinetic isotope effects), X-ray crystallography, site-directed mutagenesis, proteomics, and high-throughput screening. There are many interactions with core facilities and center programs on campus.
SIGNIFICANCE
Understanding the enzymology involved in the reactions of drugs, steroids, etc. is very relevant to treatment of human diseases. Knowledge and approaches developed in this laboratory have been applied extensively in drug development and safety assessment with drugs, including prediction of pharmacokinetics and drug-drug interactions. Some P450s (e.g., steroid aromatase (19A1), 17A1, 51A) are also established drug targets in the treatment of several maladies.
Postdoctoral Position Availability and Details: Postdoctoral positions are available to qualified individuals with backgrounds involving chemistry and biochemistry, with emphasis on quantitative skills. Please submit a CV and three letters of recommendation.