Research Abstracts Online
January 2009 - March 2010
Mayo Clinic College of Medicine
Department of Physiology and Biomedical Engineering
PI: James R. Thompson
Enhancers of Dihydrolipoamide Dehydrogenase Stability and Function
Dihydrolipoamide dehydrogenase (DLD) is a mitochondrial enzyme with moonlighting functions as a protease and diaphorase. Although DLD is primarily dimeric, this population coexists with a monomeric population. Significant diaphorase activity is associated with the monomer, very little activity with the dimer. Diaphorase activity directly increases oxidative stress through production of ferrous iron and hydrogen peroxide, which together undergo Fenton chemistry to produce damaging hydroxide radicals. Moreover, protease sites buried and inactive in the DLD dimer are revealed and active in the monomer with a specificity for frataxin, a mitochondrial protein critical in iron storage and detoxification. Combined, this knowledge suggests DLD is a prime target for drugs designed to reduce oxidative stress. These researchers hypothesize that by noncovalently crosslinking or stabilizing dimeric DLD, the proteolytic and diaphorase activities of monomeric DLD will decrease. To test this hypothesis, the researchers will leverage structure-based drug design to create high-affinity compounds using fragment-sized molecules. They use MSI resources for virtual screening of binding fragments as well as de novo design of potential drug leads using crystal structures of fragments bound to DLD.
Donald S. Berkholz, Research Associate