Guengerich Research Laboratory

The Guengerich laboratory is interested in the enzymes involved in the activation and processing of xenobiotic chemicals (i.e., those not normally found in the body, such as drugs and carcinogens), as well as steroids and vitamins.

Research Interests

The laboratory is currently focused on several aspects of cytochrome P450 (P450) enzymes, in work ow supported by NIH grant R35 GM151905. Our work generally involves the human P450s.

One aspect is the chemistry involved I nP450 catalysis, particularly in the context of alternate oxidant species (i.e., Fe-O complexes), particularly Compound I (FeO3+) and Compound 0 (Fe3+O2¯). Kinetic deuterium isotope measurements are also measured in some cases.

Another area of research involves the roles of intracellular binding proteins, particularly fatty acid binding protein 1 (FABP1). We have reported that FABP1 is capable of direct transfer of fatty acids to P450 4A11. Current research involves transfer of fatty acids to other P450s. FABP1 also binds some drugs and possibly carcinogens. We are investigating these systems with regard to direct transfer vs. free equilibrium competition both of which have ramifications in metabolism.

Another aspect of our P450 research involves delineation of functions of “orphan” P450s, i.e. those currently devoid of known biological  function. One particular interest is P450 27C1, a skin mitochondrial P450 involved in 3,4-desaturation of retinoids.

Another project involves a search for more selective inhibitors of P450 17A1, the enzyme involved in the biosynthesis of androgens.

Methods used in the laboratory include heterologous expression of enzymes, enzyme purification, organic synthesis, HPLC and other chromatography, several types of mass spectrometry, rapid kinetics (stopped-flow spectroscopy, rapid-quench kinetics, computational simulation and a=data fitting), X-ray crystallography, and UV-visible, fluorescence, and circular dichroism spectroscopy.