The family of Fe/Mn superoxide dismutase : structure, catalysis and therapeutic uses

Abstract

The mononuclear (iron or manganese) superoxide dismutases (SOD) have long been studied for their possible role in life extension as they remove harmful superoxide radicals. However, the involvement of superoxide in a wide range of diseases and treatments has made these SODs interesting subjects for possible therapeutic intervention. Although knock-out mutations of MnSOD are lethal, mutations in the mitochondrial leader sequence have been associated with diabetic retinopathy, neurodegenerative disease and psychiatric disorders. Furthermore the propensity for manganese SOD to sequester iron instead of manganese, given the right conditions, has brought the role of human MnSOD into focus relating to the iron homeostasis of mitochondria. In SODs, the general ping-pong mechanism of dismutation involves sequential reduction and oxidation of the metal cofactor, with the simultaneous oxidation and reduction of superoxide. The products of this reaction are hydrogen peroxide and molecular oxygen. MnSOD is regarded as both a tumor biomarker and a tumor suppressor protein and changes in the levels of MnSOD are observed in various cancer cells. Tumors associated with over-expression of MnSOD tend to be aggressive and metastatic while other tumors exhibit characteristically low levels of MnSOD. The tumor suppressor property of this protein appears to be related to the modulation of ROS and the generation of hydrogen peroxide and not only to its antioxidant capacity. Although MnSODs produced by different species exhibit structural homology, subtle differences do exist in their catalysis that in turn determine the rate at which hydrogen peroxide produced. As hydrogen peroxide is a signaling molecule that affects various pathways including kinase-driven pathways and apoptotic pathways, the level of SODgenerated hydrogen peroxide may serve as a molecular switch between the pro-survival and apoptotic cellular pathways. An understanding of the structural characteristics that determine specific kinetic profiles will help explain the anti-tumorogenic and antioxidant functions of SOD and enable the design of efficient biomimetics for therapeutic application.