The underlying goal of the research group is to provide understanding of the functional mechanisms of proteins to finally reprogram their reaction modes. Specifically, we pursue two research goals, the characterization of multienzyme proteins involved in fatty acid synthesis and their evaluation as targets for inhibition, and the use of multienzyme proteins for the synthesis of bioactive compounds.
The research activities are at the crossroads between the fields of structural biology, protein chemistry and chemical (bio)synthesis. Projects span the basic characterization of target proteins, their manipulation in structure and function, and finally their inhibition or integration into synthetic routes.
Research topic I:
Due to the complexity of the multifunctional fatty acid synthases (FAS), these proteins are poorly understood. Just recently structural studies could give first insights into the working mode of FAS. One focus in our lab is to answer the basic questions in fatty acid synthesis: How do the multifunctional FAS in the different kingdoms of life look like? Why did fatty acid synthesis in multifunctional proteins appear in nature? How do these large and complex proteins assemble from their subunits?
In addition, we are also interested in more advanced topics. As fatty acids are elementary building blocks of living organisms, the inhibition of FAS is relevant for antibiotic, antitumor and antiviral therapy. For developing strategies for selective inhibition, which means exclusive inhibition of the FAS of the pathogenic organism or the malignant cell, we use new insights from our structural and functional studies.
Research topic II:
Polyketide synthases (PKS) are similar to FAS. They are multifunctional proteins, and catalyze reactions by a similar working concept. However, as compared to FAS, the multienzymatic PKS show variations in their functional spectrum, and their products, termed polyketides, are of more complex chemistry than fatty acids. Polyketides are produced by microorganisms to mediate a growth advantage by being toxic to other (micro)organisms in the same habitat. This intrinsic high bioactivity of polyketides has been used in medicine for decades to target acute and degenerative diseases. Erythromycin, epothilone or rapamycin are just a few of the currently used drugs.
In this research focus, we study PKS and their catalytic potential. Our ultimate goal is to train these proteins to synthesize variations of the natural compounds, and, thus, to establish protein-mediated synthesis of polyketides as a tool in modern synthetic chemistry. For realization, we work on improved methods for manipulation and expression of PKS, and on establishing and refining structure-function relationships in PKS for efficient reaction control.
Figure: Raising the veil of protein function. The knowledge about proteins is constantly increasing making protein engineering a valuable tool for enlarging the repertoire of protein function. In our research, we use state of the art methods to analyze molecular mechanisms of proteins to make them accessible to chemical and biotechnological applications.