Potent Anti-tumor Effects of an Active Site Mutant of Human Manganese-Superoxide Dismutase

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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-03, Vol.279 (13), p.12769-12776
Main Authors: Davis, Christopher A., Hearn, Amy S., Fletcher, Bradley, Bickford, Justin, Garcia, Jorge E., Leveque, Vincent, Melendez, J. Andres, Silverman, David N., Zucali, James, Agarwal, Anupam, Nick, Harry S.
Format: Article
Language:English
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Summary: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 H2O2.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M310623200