Research Projects (Third party funds)
Exploring and Controlling Phenanzine Biosynthesis with Chemical Biology
The phenazines are a large class of redox-active bacterial secondary metabolites that play an important role for cell survival by acting as antibiotics and virulence factors. Their biosynthesis may therefore be an interesting target for novel pharmaceuticals in the treatment of infectious disease.Phenazines derive from chorismic acid through a conserved pathway that involves enzymes encoded in the phz-operon. Despite progress in the general understanding of the process, important details are still unclear due to the fact that phenazine biosynthesis proceeds through several unstable intermediates that are difficult to characterize. This is a collaborative project between Rolf Breinbauer (Organic Chemistry, Graz Technical University, Austria) and Wulf Blankenfeldt (Structural Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany) and aims at filling the existing gaps by combining synthetic chemistry with biochemical and structural techniques.
In particular, we
(1) investigate differences between 2-amino-2-desoxyisochorismate (ADIC) synthase PhzE and the related anthranilate synthases, which convert ADIC further to anthranilate despite having a very similar active center;
(2) want to gain detailed insight into PhzF, which catalyzes a [1,5]-prototropic shift that may follow a pericyclic reaction mechanism;
(3) develop existing product analogues of PhzB into inhibitors of phenazine biosynthesis and
(4) understand the biochemical relevance of PhzA/PhzB heterodimerization in pseudomonal phenazine producers.
- Structure and Function of Proteins - Prof. Wulf Blankenfeldt
DFG - German Research Foundation