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  • Undergraduate Poster Abstracts
  • FRI-615 ALTERED ELECTRON TRANSFER KINETICS IN NATURALLY NOT OCCURRING 2C8 POLYMORPHIC VARIANTS

    • Kimberly Sam ;
    • William Arnold ;
    • Susan Zelasko ;
    • Daryl Meling ;
    • Aditi Das ;

    FRI-615

    ALTERED ELECTRON TRANSFER KINETICS IN NATURALLY NOT OCCURRING 2C8 POLYMORPHIC VARIANTS

    Kimberly Sam, William Arnold, Susan Zelasko, BS1, Daryl Meling, Aditi Das.

    University of Illinois, Urbana-Champaign, Urbana, IL.

    Cytochrome P450 2C8 (CYP 2C8) is an extrahepatic enzyme that plays a significant role in the metabolism of over 20% of clinically relevant drugs, including paclitaxel, an anticancer drug used to treat ovarian, breast, and lung cancers, as well as Kaposi sarcomas. It has been noted that naturally occurring polymorphic variants CYP 2C8*2 and CYP 2C8*3 have prevalence in African American and Caucasian populations at 18% (*2) and 13% (*3) respectively. It is believed that the mutations lie within the putative binding interface between CYP 2C8 and its redox partner, cytochrome P450 reductase (CPR). The location of these mutations plays a critical role in the efficiency of the protein, as previous studies have shown reduced substrate hydroxylation due to inefficient use of electrons toward the production of reactive oxygen species. To quantify the inefficient use of electrons, we measured the amount of hydrogen peroxide formed using nanodisc technology to study membrane protein function in the native-like bilayer environment. Additionally, the electron transfer rates between the CYP 2C8 variants and CPR were determined through stopped-flow studies to better understand how these mutations alter electron flow. Hydrogen peroxide production and altered electron transfer rates were observed in both CYP 2C8*2 and CYP 2C8*3 in comparison to the wildtype, demonstrating that these mutations have a significant effect on the enzyme efficiency. The results of these studies propose therapeutic potentials that will allow for the development of drugs that better fit populations carrying these variants.