National Institute of General Medical Sciences 5R01GM145647-05

Deciphering the Enzymatic Mechanism of Superoxide Dismutase

This award funds research to understand the enzymatic mechanism of manganese superoxide dismutase (MnSOD) using neutron crystallography and complementary methods to reveal proton positions and electron-proton transfer processes critical for dismuting superoxide, with implications for diseases involving oxidative stress.

Description

Superoxide dismutase (SOD) enzymes are essential to life and reduce the level of reactive oxygen species in cells. Abnormal SOD activity is found in many pathologies, such as cancer, neurodegenerative diseases, and cardiovascular dysfunction. To provide a detailed understanding of SOD in diseases and for the design of therapeutic interventions, our investigation seeks to define the atom-by-atom workings of the group of enzymes for the first time. Our research aims to understand the molecular basis of how MnSOD uses coupled proton-electron transfers to dismute superoxide. Recent advancements with neutron crystallography at Oak Ridge National Laboratory have allowed high-detail proton position determination, overcoming limitations of X-ray crystallography. The neutron maps will reveal proton relays to the active site metal and the protonation states of metal-bound ligands. The hypothesis is that MnSOD transfers protons from water molecules via amino acids to the manganese for dismutation of superoxide to hydrogen peroxide and oxygen via cyclic redox reactions. Specific aims include characterizing the electron-coupled proton relays by investigating the proton environment of the resting states of the manganese active sites, the Mn-peroxo complex, and the superoxide-bound enzyme. Spectroscopy and computational chemistry will complement crystallography to interpret enzymatic activity. The results will be of interest to structural biology, antioxidants, and metallo-enzymology fields.

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