Dorothea Fiedler

+49 30 94793 151


Office A 3.08































Department Chemical Biology I (Dorothea Fiedler)


Our group seeks to develop a better understanding of the multiple ways in which nature utilizes phosphate in both protein signaling cascades and metabolic networks. Signaling and metabolic pathways are very complex, but the individual steps within these cascades depend on simple chemical reactions and often involve the reversible addition of phosphoryl groups. Because deregulation of cellular information transfer is associated with a wide range of diseases, a detailed annotation of signaling events in healthy and diseased states can help to highlight new avenues for therapeutic intervention. Specifically our research focuses on the following areas:

1) Signaling functions of inositol pyrophosphate messengers in metabolic disorders

2) The role of inorganic phosphate in cancer metabolism and metastasis

3) Activity based probes for profiling serine-threonine phosphatases in cancer progression

Common to all projects is our multi-disciplinary approach. We use techniques in inorganic and organic chemistry, chemical genetics and genetics, molecular biology and proteomics. By tackling each of these intriguing questions in an interdisciplinary fashion, our program provides a great training experience for the students and postdocs in the lab. Signaling functions of inositol pyrophosphate messengers in metabolic disorders:The rapid turnover of inositol pyrophosphates (PP-IPs) in cells has lead to the hypothesis of an “inositol pyrophosphate code,” in which the temporally and spatially controlled production of these high-energy messengers dictates distinct downstream signaling events. Genetic perturbation of PP-IP signaling in mammals revealed severe defects in insulin signaling and body weight regulation, but the underlying molecular mechanisms have remained elusive. Our lab has developed non-hydrolyzable PP-IP analogs, and has demonstrated the utility of these analogs for interrogating the distinct PP-IP signaling mechanisms: protein binding and protein pyrophosphorylation, a new post-translational modification. To probe the biological relevance of protein pyrophosphorylation, we have devised a convenient synthetic approach to generate pyrophosphopeptides. These peptides will be used to optimize enrichment and detection methods for pyrophosphopeptides and –proteins in complex mixtures. In a parallel effort, we have implemented a chemical genetic approach to selectively inhibit various PP-IP biosynthetic enzymes. Our long-term objective is to evaluate and combine these tools in insulin responsive cell lines to provide a comprehensive picture of PP-IP signaling, its central role in maintaining cell homeostasis, and its deregulation in metabolic disorders. The role of inorganic phosphate in cancer metabolism and metastasis:Rapidly dividing cells rely on a constant supply of nutrients. Phosphate is a key component for the synthesis of biomolecules and we hypothesize that tumor cells exhibit an increased demand for phosphate to sustain growth and proliferation. To study the phosphate uptake ability of tumor cells, our lab has designed a fluorescent sensor to measure phosphate concentrations in living cells. The boron-based sensors are water soluble, charge neutral, and thus cell-permeable, and bind to phosphate with a low millimolar dissociation constant. We are also using global and targeted metabolomics to observe cellular metabolites in response to changes in phosphate availability. These methods are employed in a panel of breast cancer cell lines to determine the degree of phosphate dependent metabolic rewiring.

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)

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