Abstract
Superoxide dismutases (SODs) are necessary antioxidant enzymes that protect cells from reactive oxygen species (ROS). Decreased levels of SODs or mutations that affect their catalytic activity have serious phenotypic consequences. SODs perform their bio-protective role by converting superoxide into oxygen and hydrogen peroxide by cyclic oxidation and reduction reactions with the active site metal. Mutations of SODs can cause cancer of the lung, colon, and lymphatic system, as well as neurodegenerative diseases such as Parkinson’s disease and amyotrophic lateral sclerosis. While SODs have proven to be of significant biological importance since their discovery in 1968, the mechanistic nature of their catalytic function remains elusive. Extensive investigations with a multitude of approaches have tried to unveil the catalytic workings of SODs, but experimental limitations have impeded direct observations of the mechanism. Here, we focus on human MnSOD, the most significant enzyme in protecting against ROS in the human body. Human MnSOD resides in the mitochondrial matrix, the location of up to 90% of cellular ROS generation. We review the current knowledge of the MnSOD enzymatic mechanism and ongoing studies into solving the remaining mysteries.
Highlights
Superoxide (O2 − ) is a potent oxidizing agent
Density function theory (DFT) calculations performed by Jackson and co-workers with E. coli to perform enzymatic efficiently shuttle protonsbetween to the active indicate that the its active site with function azide adducts exists initamust dynamic equilibrium and six coordinate states transfer at 296 K
In nuclear magnetic resonance (NMR) studies of E. coli FeSOD by the Miller group, azide did not Tobind date, insight into theofproton-based mechanism has was come from indirect observations
Summary
Superoxide (O2 − ) is a potent oxidizing agent. Excessive amounts lead to a cascade of reactions causing damage to important biological macromolecules such as DNA, lipids, and proteins. To protect cells from harmful amounts of superoxide, SODs convert two superoxide anions to oxygen and hydrogen peroxide using a cyclic reduction and oxidation reaction of the active site metal. This redox shuffling of the active site metal to perform catalysis, called dismutation, is dependent on two protons per cycle. The atomic mechanism has been elusive because of (1) the fast reaction rate of MnSOD; (2) the high reactivity and short half-life of superoxide; and (3) the difficulties in detecting protons and protonation states of amino acids in an enzyme [12,13]. Several articles review other SOD mechanisms [4,14,15]
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