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  • Stanley V. Smith, PhD

     stan_smith.jpg Assistant Professor
    Office: R401
    Lab: R402
    Phone:(601) 815-1268
    E-mail: SVSmith@umc.edu

    Current research

    My primary research interests are in the areas of protein structure and dynamics, and how their interplay regulates protein function in biological environments. My research is focused on the cytochrome P450s, a superfamily of hemeprotein enzymes. The cytochrome P450s bind molecular oxygen and use it to oxidize substrates.

    Mammalian P450s are membrane-associated and are involved in the metabolism of xenobiotics such as drugs and pesticides, and synthesis and metabolism of endogenous compounds such as steroids and fatty acids. In humans, the P450s are directly involved in processes leading to illness and disease by playing prominent roles in drug/xenobiotic-induced toxicity, drug-drug interactions, and generation of toxic or reactive intermediates. The hepatic P450s are of particular interest because they are involved in the biotransformation pathways of the majority of the clinically prescribed drugs. While the P450 superfamily of enzymes collectively catalyze a variety of reactions using a diverse array of structurally distinct substrates, the individual forms of P450 have unique yet often overlapping substrate specificity profiles. The goal of my research is to ascertain the structural features and molecular mechanisms that govern the functional properties of clinically relevant mammalian P450s. This knowledge will lead to more insightful approaches to predicting and controlling P450 activities and ultimately to ways of making the activity profiles more beneficial to the host.

    In addition to the hepatic P450s, research efforts are also directed towards understanding structure/function relationships in the breast cancer molecular target aromatase (P450 19A1). Several clinically prescribed drugs inhibit this enzyme and help stop cell proliferation in estrogen receptor positive breast cancers. It is a novel P450 in that its catalytic cycle involves a complex three-step mechanism through which it converts androgens to estrogens. Studies are underway aimed at understanding how the unique features of aromatase might allow for a targeted design of novel chemical entities that disrupt activity of this enzyme. The ultimate goal of these studies is to identify novel chemical entities with unique aromatase binding and inhibition properties.

    Selected publications

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    • Smith, S.V., Koley, A.P., Dai, R., Robinson, R.C., Leong, H., Markowitz, A., and Friedman, F.K. Conformational Modulation of Human Cytochrome P450 2E1 by Ethanol and Other Substrates: A CO Flash Photolysis Study. Biochemistry, 39(19): 5731-5737, 2000. PubMed link
    • Omata, Y., Dai, R., Smith, S.V., Robinson, R.C. and Friedman, F.K. Synthetic Peptide Mimics of a Predicted Topographical Interaction Surface: the Cytochrome P450 2B1 Recognition Domain for NADPH-cytochrome P450 Reductase. J. Protein Chemistry, 19(1):23-32, 2000. PubMed link
    • Piro, M.C., Militello, V., Leone, M., Gryczynski, Z., Smith, S.V., Brinigar, W.S., Cupane, A., Friedman, F.K., and Fronticelli, C. Heme Pocket Disorder in Myoglobin: Reversal by Acid-Induced Soft Refolding. Biochemistry, 40(39): 11841-50, 2001. PubMed link
    • Smith, S.V., Robinson, R.C., Smith, T.G., Burks, S.M., and Friedman, F.K. Rapid Conformational Dynamics of Cytochrome P450 2E1 in a Natural Biological Membrane Environment. Biochemistry, 45(51): 15617-23 2006. (selected "Hot Article", Biochemistry, January, 2007). PubMed link