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Structural characterization of human UDP-glucose dehydrogenase reveals novel insights into regulatory modes of the enzyme
UDP-glucose Dehydrogenase (UGDH) converts UDP-glucose to UDP-glucuronate. UDP-glucuronate pools are critical for hyaluronan (HA) and other glycosaminoglycan (GAG) biosynthesis as well as steroid elimination from the cell. UGDH function is required for several cellular processes including heart valve development. It was found that patients heterozygous for either E416D or R141C point mutations in the UGDH protein sequence exhibited cardiac edema. Through structural and biophysical characterization of these mutants we identified oligomeric assembly to be a critical regulator of UGDH function. Further analysis using experimentally controlled quaternary structure mutants revealed novel insights into the structural regulation of the enzyme. UGDH is a homohexamer comprised of a trimer of dimers. Utilizing tools such as analytical size exclusion chromatography, enzyme kinetics and limited proteolysis, we determined that assembly and disassembly of UGDH into its hexameric and dimeric counterparts, respectively, is critical for activity and function. This novel mode of regulation may be useful for designing targeted inhibitors or activators of UGDH in vivo.
Hyde, Annastasia S, "Structural characterization of human UDP-glucose dehydrogenase reveals novel insights into regulatory modes of the enzyme" (2014). ETD collection for University of Nebraska - Lincoln. AAI3618765.