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 the development of new drugs against protozoan parasites. The current project pursues the goal to obtain a comprehensive description of the allosteric mechanisms regulating UDP-sugar pyrophosphorylases in the Trypanosomatidae family of parasites. This information is then 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 is used that allows 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 is funded by DFG (GZ: FE 1510/2-1) and Hochschulinternen Leistungsförderung Program (HiLF), Hannover Medical School.
The innate immune sensors activate interferon-driven antiviral responses upon recognition of PAMPs and serve as a rheostat for the metabolic activity of the microbiota and its exposure to diet, xenobiotics, and infections. The ability to modulate innate immune sensors opens new ways to novel anti-viral and anti-inflammatory drugs, and therapies against cancer and many aging-associated metabolic, neoplastic, autoimmune or autoinflammatory disorders. Using unbiased experimental screening combined with computer-aided rational drug design approaches, we aim at developing small-molecule allosteric effectors that specifically enhance or reduce the enzymatic activity of members of the family of innate immune sensors, such as cyclic GMP-AMP synthases (cGAS) and 2'-5' oligoadenylate synthetases (OAS).This project is funded by the Cluster of Excellence RESIST - Resolving Infection Susceptibility (EXC 2155 - grant TP B11, project ID: 39087428).
In this project, the kinetic states and conformational changes associated with substrate binding and product release mechanisms of innate immune sensors cGAS and OAS are investigated by combining three advanced cutting-edge methodologies: time-resolved serial femtosecond crystallography, on-chip substrate or product binding studies, and high-pressure crystallography. The obtained mechanistic information will be used to develop specific allosteric activity modulators of innate immune sensors. The project is funded by the Cluster of Excellence RESIST - Resolving Infection Susceptibility.