F. Peter Guengerich
Major areas of interest include the metabolism of carcinogens and drugs by cytochrome P450 enzymes, the bioactivation of halogenated hydrocarbons, and polymerase interactions with carcinogen-modified DNA. Several approaches are being used to understand the catalytic mechanisms of the human cytochrome P450 enzymes, including site-directed and random mutagenesis, kinetic analysis, isotope effects, and substrate-activity relationships. One major area of interest is the identification of reactions catalyzed by the “orphan” P450s, those in humans and also Streptomyces that do not have characterized functions yet. Work on halogenated hydrocarbons is done with trichloroethylene, ethylene dibromide, and methylene dihalides and the adducts they form. Glutathione transferase-mediated bioactivation is under investigation, as well as in the case of some bifunctional electrophiles. Studies on the polymerases involve the use of modified oligonucleotides, steady-state and pre-steady-state kinetics, and physical approaches such as x-ray diffraction. A major goal is to understand how carcinogen-DNA adducts cause polymerases to stall and misincorporate bases.