Function of active site residues in the dUTPase from Epstein‐Barr Virus

Abstract

Epstein‐Barr Virus, which causes infectious mononucleosis, contributes to many diseases such as Burkitt lymphoma and other cancers. The viral genome encodes a dUTPase, an enzyme that catalyzes the reaction of dUTP + H2O to dUMP + PPi + H+. This is an intermediate reaction involved in the formation of the thymidine nucleotide. The dUTPase found in humans is a trimeric enzyme containing three active sites while the viral enzyme is monomeric. Due to variation in the structures of the human and viral proteins, there may be differences in each enzyme's catalytic activity. Our results demonstrate the importance of a metal cofactor for activity of the viral enzyme. The role of active site residues in substrate binding and the catalysis of dUTP to dUMP is being examined by site‐directed mutagenesis. Characterization of the EBV dUTPase may facilitate the discovery of inhibitors. Inhibition of dUTPase decreases the formation of thymidine nucleotides creating a high dUTP/dTTP ratio. Uracil becomes incorporated into DNA in place of thymine which causes mutations that may be detrimental to cell survival. Selectively inhibiting the dUTPase from Epstein‐Barr Virus provides a mechanism to target cells infected with the virus without damaging uninfected cells.Support or Funding InformationUWL Undergraduate Research and Creativity GrantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.