SUPEROXIDE-DRIVEN ACONITASE FE-S CENTER CYCLING

O-2(-) produced by the autoxidation of respiratory chain electron carr iers, and other cellular reductants, inactivates bacterial and mammali an iron-sulfur-containing (de)hydratases including the citric acid cyc le enzyme aconitase. Release of the solvent-exposed iron atom and oxid ation of the [4Fe-4S](2+) cluster accompanies loss of catalytic activi ty. Rapid reactivation is achieved by iron-sulfur cluster reduction an d Fe2+ insertion. Inactivation-reactivation is a dynamic and cyclical process which modulates aconitase and (de)hydratase activities in Esch erichia coli and mammalian cells. The balance of inactive and active a conitase provides a sensitive measure of the changes in steady-state O -2(-) levels occuring in living cells and mitochondria under stress co nditions. Aconitases are also inactivated by other oxidants including O-2, H2O2, NO., and ONOO- which are associated with inflammation, hype roxia and other pathophysiological conditions. Loss of aconitase activ ity during oxidant stress may impair energy production, and the libera tion of reactive iron may further enhance oxidative damage. Iron-sulfu r center cycling may also serve adaptive functions by modulating gene expression or by signaling metabolic quiescence.