Allosteric regulation of UDP-sugar pyrophosphorylases as a means to develop new anti-parasitic treatments

• Applicant: Dr. Roman Fedorov
• Subject Area: Biochemistry ; Biophysics ; Structural Biology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282955187

UDP-sugar pyrophosphorylases play a central role in cellular carbohydrate biosynthesis. As metabolic switches UDP-sugar pyrophosphorylases are subject to elaborate regulatory mechanisms. Elucidating these mechanisms is essential for the fundamental understanding of cellular carbohydrate biosynthesis and for the development of new concepts to specifically inhibit individual enzymes. Due to their central position in carbohydrate biosynthesis and species-specific differences, UDP-sugar pyrophosphorylases are attractive targets for development of new drugs against protozoan parasites. The current research program pursues the goal to obtain a comprehensive description of the allosteric mechanisms regulating UDP-sugar pyrophosphorylases in the Trypanosomatidae family of parasites. This information will be used to identify the sources of specific inhibition of Trypanosomatidae enzymes, providing ways to new anti-parasite treatments. To achieve these objectives, a multifaceted approach will be used that will allow us to combine structural information about various kinetic states of UDP-sugar pyrophosphorylases with kinetic and hydrodynamic data as well as relating the structural and kinetic consequences of specific mutations to the in vivo function of these enzymes. The project builds on preliminary results that confirm the feasibility of our work program.

• DFG Programme: Research Grants