Impact of Homocitrate Synthase on Aspergillus fumigatus pathogenesis

Felicitas Schöbel* and Matthias Brock.

Author address: 

Leibniz Institute for Natural Product Research and Infection Biology Hans Knöll Institute, Jena

Abstract: 

Fungi, such as A. fumigatus, are able to synthesize lysine de novo via the alpha-aminoadipate pathway. In contrast, lysine is an essential amino acid for humans and must be obtained from the diet. Therefore, enzymes of this pathway might represent potential targets for new antifungals. However, until now it is unclear, whether A. fumigatus can satisfy its need for lysine from the degradation of the surrounding host tissue, e.g. from the degradation of proteins. This assumption is supported by the virulence attenuation of an A. fumigatus methylcitrate synthase mutant in murine infection models (Ibrahim-Granet et al 2008). Such a mutant accumulates toxic amounts of propionyl-CoA, which most likely derive from the degradation of proteins during pathogenesis. Our major interest was to verify, whether the de novo synthesis of lysine is only essential for the onset of an invasive aspergillosis or also during later stages of infection. To prove this assumptions, we deleted the homocitrate synthase, the first enzyme of the alpha-aminoadipate pathway, from the genome of A. fumigatus. The mutant revealed that the de novo lysine biosynthesis plays a critical role for conidia germination on unhydrolysed proteins. In vivo studies confirmed an importance of lysine biosynthesis especially during the onset of infection, whereas the phenotype was partially complemented by feeding mice with elevated levels of lysine. Ibrahim-Granet O., et al. (2008) Methylcitrate synthase from Aspergillus fumigatus is essential for manifestation of invasive aspergillosis. Cell Microbiol.; 10(1):134-48. *Student poster
2009

abstract No: 

47

Full conference title: 

6th International Aspergillus Meeting
    • Asperfest 6 (2009)