Potent anti-tumor effects of an active site mutant of human manganese-superoxide dismutase: Evolutionary conservation of product inhibition

Academic Article

Abstract

  • Mn-SOD serves as the primary cellular defense against oxidative damage by converting superoxide radicals (O2.-) to O2 and H2O2. A unique characteristic of this mitochondrial anti-oxidant enzyme is the conservation from bacteria to man of a rapidly formed product inhibited state. Using site-directed mutagenesis, we have generated an active site mutant (H30N) of human Mn-SOD, which exhibits significantly reduced product inhibition and increased enzymatic efficiency. Overexpression of the H30N enzyme causes anti-proliferative effects in vitro and anti-tumor effects in vivo. Our results provide a teleological basis for the phylogenetically invariant nature of position His-30 and the evolutionary conservation of product inhibition. These data also provide more direct intracellular evidence for the signaling role associated with H 2O2.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Davis CA; Hearn AS; Fletcher B; Bickford J; Garcia JE; Leveque V; Melendez JA; Silverman DN; Zucali J; Agarwal A
  • Start Page

  • 12769
  • End Page

  • 12776
  • Volume

  • 279
  • Issue

  • 13