Structural and biochemical studies on the mechanism of CO2-sensing in the virulence of pathogenic fungi

• Applicant: Professor Dr. Clemens Steegborn
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2006 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 27482036

Carbon dioxide (CO2) can act as a signalling molecule and e.g. enables mosquitos to find their prey. A CO2-sensing system is also involved in the human-pathogenic fungi C. albicans and C. neoformans in switching from growth in a natural environment (~0.03 % CO2) to virulent growth in the host (~5 % CO2). The mechanisms how organisms detect and respond to CO2 are largely unknown. Recently, however, an adenylyl cyclase and a carbonic anhydrase were identified as components of the fungal CO2-sensing system. The fungal adenylyl cyclases were found to be sensitive to bicarbonate, the product of the reaction catalyzed by carbonic anhydrases. Knocking out either enzyme prevents fungal pathogenesis under certain conditions suggesting the enzymes involved as targets for anti-fungal drugs. We plan to study this signalling system by using biochemical methods and protein crystallography. We will determine structures of the fungal enzymes in complex with various ligands. We plan to exploit their unique molecular characteristics for the structure-based development of highly specific inhibitors which will be used for physiological studies on fungal pathogenesis. We will also study further mechanistic details of adenylyl cyclase regulation by ¿-class carbonic anhydrases, especially the anticipated interaction of the two enzymes. This work should reveal unique features of this signalling pathway which could be targeted by novel therapies.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1160: Colonisation and Infection by Human-pathogenic Fungi