Scott

Emily Scott
Assistant Professor
Department of Medicinal Chemistry

Structure-Function Relationships in
Cytochromes P450 from the
2A and 2E Subfamilies

Cytochromes P450 perform the first step in eliminating a wide range of xenobiotics, including drugs, environmental contaminants, and procarcinogens. P450s from families 1, 2, and 3 act on distinct yet overlapping sets of diverse substrates. The molecular interactions giving rise to differential metabolism are largely undefined but are a vital prerequisite for predicting drug metabolism in vivo. Our long-term goal is to generate a database of P450-ligand interactions that can be used in a predictive manner. The goal of this proposal is to elucidate the structural basis for the differing but overlapping substrate specificities of human 2A and 2E P450s. The hypothesis is that since both common and distinct substrates are metabolized, only a few specific interactions distinguish the metabolic capabilities of these two P450 subfamilies. Identifying those interactions is a first step toward predictive metabolism of important drug candidates and environmental xenobiotics. First, active site residues orienting marker substrates in 2A6, 2A13, and 2E1 will be identified.
		A combination of site-directed mutagenesis and analysis with common and differential substrates will be used to identify interactions responsible for distinct vs. overlapping metabolism.Second, we propose to generate a molecular structure from either the P450 2A or 2E subfamilies.
Proteins from these subfamilies will be modified to increase solubility and characterized for their aggregation state, stability, and function. Promising candidate(s) will be the subject of crystallization trials with the intent to determine a high-resolution x-ray structure. Comparison of ligand interactions both between the 2A and 2E enzymes and with better characterized P450s from other subfamilies is expected to yield substantial insights into P450 structure-function diversity. This work will significantly enhance our ability to elucidate mechanisms of differential metabolism and inhibition between human P450s with potential impact on drug design, incidence of adverse drug-drug interactions, and prevention of and intervention in human carcinoma. Dr. Scott graduated from the COBRE in 2007 when she was awarded an NIH R-01 grant " Structural Basis of Cytochrome P450 2A13 Activity."
Copyright © 2008 Center for Biomedical Research Excellence in Protein Structure and Function Department of Medicinal Chemistry, School of Pharmacy The University of Kansas Contact webmaster with comments about this web site.