Journal of Biological Chemistry
Volume 279, Issue 13, 26 March 2004, Pages 12769-12776
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Enzyme Catalysis and Regulation
Potent Anti-tumor Effects of an Active Site Mutant of Human Manganese-Superoxide Dismutase: EVOLUTIONARY CONSERVATION OF PRODUCT INHIBITION*

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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.

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*

This work was supported by funding from the University of Florida Shands Cancer Center, National Institutes of Health Grants R01 HL39593 (to H. S. N.), R01 GM54903 (to D. N. S.) and an American Lung Association fellowship (to A. S. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.