Contact

Dorothea Fiedler

+49 30 94793 151

fiedler(at)fmp-berlin.de

Office A 3.08

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Department Chemical Biology I (Dorothea Fiedler)

Research

Cells are able to receive cues about their environment, evaluate their internal energy status, and then adjust their behavior accordingly. These decision-making processes require an integration of the metabolic machinery with cellular signaling networks. The integration is often mediated by metabolic messengers, which can influence protein modifications, gene expression, and signal transduction. Our group focusses on a group of metabolic messengers termed inositol poly- and pyrophosphates. These highly phosphorylated molecules come in many different flavors and have been linked to metabolic diseases such as obesity and type 2 diabetes, cancer and ageing. While these links have been clearly established by genetic studies, a molecular understanding of the regulation by inositol poly- and pyrophosphates is still lacking. It has thus been the goal of the lab to develop new chemical and biochemical tools that will provide a mechanistic picture of inositol phosphate signaling, so that this pathway can be rationally exploited for therapeutic purposes in the long run. To do so, we apply an interdisciplinary approach, using techniques in chemical synthesis, peptide synthesis, biochemistry, proteomics, metabolomics, and cell biology.

To provide a granular analysis of the messenger functions of inositol poly- and pyrophosphates, new methods are required to:

  • detect and quantify these spectroscopically silent, and structurally highly related molecules
  • interrogate the enzymes involved in inositol phosphate biosynthesis and catabolism and perturb cellular inositol phosphate concentrations
  • probe their modes of action mechanistically

We have begun to address these challenges by developing 13C-labeled inositol and 13C-labeled inositol phosphates which can be used for physico-chemical characterization of inositol phosphates, real-time biochemical analyses, and metabolic labeling of intact cells. We have also implemented large-scale screening to identify inhibitors of inositol kinases, and have identified cell-penetrating peptides that can deliver inositol phosphates into cells. For mechanistic studies, we have employed non-hydrolyzable, multiplexed inositol phosphate affinity reagents in various contexts, and have established a mass spectrometry approach to identify pyrophosphorylated proteins, a modification thought to be mediated by high-energy inositol pyrophosphates.

We currently employ this suite of tools - in many cases in collaboration with labs with diverse biological backgrounds - to understand different aspects of inositol (pyro-)phosphate signaling, such as:

  • the role of inositol pyrophosphates in phosphate sensing in plants
  • the contribution of inositol pyrophosphates to chromosome segregation in fission yeast
  • the function of inositol pyrophosphates in cancer progression

In the future, it is planned to expand the arsenal of chemical tools, to include reagents for organelle-specific delivery of these negatively charged metabolites, to develop an imaging approach for inositol poly- and pyrophosphates, and to broaden our scope to additional high-energy metabolic messengers, such as phosphoenolpyruvate and 1,3-bisphosphoglycerate. Only a detailed analysis of the signaling/metabolism interface will provide the most promising drug targets to treat widespread metabolic disease, such as cancer and obesity.

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)
info(at)fmp-berlin.de

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