November 13, 2018
Biochemistry and Molecular Biophysics Seminar welcomes Peter Guengerich from Vanderbilt University
Fred Peter Guengerich, professor and Tadashi Inagami Chair in Biochemistry at Vanderbilt University School of Medicine, is the featured speaker for Biochemistry and Molecular Biophysics Seminar at 4 p.m. Wednesday, Nov. 14, in 120 Ackert Hall. He will present "Regulation of Cytochrome P450 Enzymes by Reversible Oxidation of Thiols to Sulfenic Acids."
Guengerich earned his doctorate at Vanderbilt and was a postdoc at the University of Michigan. His research is on cytochrome P450 enzymes, which are responsible for the majority of drug metabolism and xenobiotic detoxification. His lab pioneered biochemical research on mammalian cytochrome P450s and were the first to purify and characterize the human enzymes. He has received many awards including the Society of Toxicology Merit Award for career achievements and the ASBMB William C. Rose Award for biochemistry research and mentoring. He is coauthor of more than 600 papers and is among the most cited researchers in biochemistry and pharmacology. He is a fellow of the American Academy of Sciences.
Presentation abstract: Cytochrome P450 (P450) enzymes are the major catalysts involved in the metabolism of drugs, steroids, fat-soluble vitamins, carcinogens, and industrial pollutants. Human P450 Family 4 enzymes and some other P450s are redox sensitive, showing a loss of activity resulting from incubation with H2O2 and recovery with mild reducing agents (1, 2). This inhibition is due to sulfenylation (Cys-SOH) of the heme-thiolate ligand, as determined by chemopreoteomic and spectral techniques (1). Interestingly, human P450 1A2 was determined to be redox insensitive. To determine the mechanism behind this redox sensitivity, molecular dynamics (MD) simulations were employed using the crystal structure of rabbit P450 4B1 (3). Mouse P450 4b1 was found to be sulfenylated in kidney microsomes and shares 85 percent identity with its human and rabbit homologs. This includes an identical amino acid sequence surrounding the heme-thiolate cysteine. In simulating either the thiolate (Cys-S-) or the sulfenic acid at the heme-ligation site, MD simulations revealed Gln-451 in either an "open" or "closed" conformation, respectively, between the cytosol and heme-thiolate cysteine. Mutation to either a leucine (Q451L) or glutamate (Q451E) abrogated the redox sensitivity, suggesting that this "open" conformation allows for reduction of the sulfenic acid and thiolate religation to the heme iron.
1. Albertolle, M., Phan, T. T. N., Pozzi, A., and Guengerich, F. P. (2018) Sulfenylation of human liver and kidney microsomal cytochromes P450 and other drug metabolizing enzymes as a response to redox alteration. Mol. Cell. Proteomics 17, 889-900
2. Albertolle, M. E., Kim, D., Nagy, L. D., Yun, C. H., Pozzi, A., Savas, Ü., Johnson, E. F., and Guengerich, F. P. (2017) Heme-thiolate sulfenylation of human cytochrome P450 4A11 functions as a redox switch for catalytic inhibition. J. Biol. Chem. 292, 11230-11242
3. Hsu, M. H., Baer, B. R., Rettie, A. E., and Johnson, E. F. (2017) The crystal structure of cytochrome P450 4B1 (CYP4B1) monooxygenase complexed with octane discloses several structural adaptations for w-hydroxylation. J. Biol. Chem. 292, 5610-5621