Associated Faculty, Chemistry
Frick Lab, 229
Cells are able to process an enormous amount of information about their environment and their internal status via highly regulated signaling pathways. Small molecule second messengers (for example cAMP, Ca2+, and nitric oxide) are an important component of signal transduction cascades. These second messengers are diffusible signaling molecules, which can be rapidly generated or released to then regulate the activity of particular effector proteins. Our lab focuses on two classes of metabolic second messengers, namely the diphosphoinositol polyphosphates (PP-IPs) and inorganic polyphosphates (polyP), because these molecules harness a recurring theme in signaling: phosphate groups.
A recently discovered group of eukaryotic second messengers are the highly phosphorylated inositides. Among the many derivatives of the inositol phosphate messengers is a subgroup that possesses high energy diphosphate groups. This intriguing class of diphosphoinositol polyphosphates (PP-IPs) has been linked to several cellular functions such as telomere maintenance, vesicular trafficking, and protein phosphorylation. Moreover, it has been demonstrated that the PP-IPs are intimately involved in insulin secretion, glucose uptake, and the metabolic state of cancer cells.
Inorganic polyphosphate (polyP) is a linear polymer in which tens to hundreds of phosphate residues are linked by phosphoanhydride bonds. The biological functions of polyP have mainly been investigated in microorganisms, although evidence is accumulating that polyP carries many important functions in mammalian systems. These functions include blood coagulation, osteoblast calcification, and breast cancer cell proliferation.
To date many of the signaling functions of PP-IPs and polyP have remained elusive, because these metabolites are difficult to study with standard cell biology techniques. Their chemical tractability, however, provides the unique opportunity to investigate their functions with chemical tools. With these probes we hope to be able to answer the following questions: Which proteins interact physically with PP-IPs? Which proteins are phosphorylated by PP-IPs? What are the metal-binding properties of PP-IPs? How are PP-IPs linked to cellular energy homeostasis? Which proteins are involved in polyP biosynthesis? Which proteins interact physically with polyP? How does polyP interact with specific metal cations? Can we use polyP for the bioremediation of toxic metals?
Investigating these problems requires an interdisciplinary approach that combines synthetic organic and inorganic chemistry with biochemical analyses and molecular and cellular biology techniques. Initial efforts will focus on understanding the molecular signaling mechanisms by employing chemical reagents. These reagents are then to be evaluated in the relevant cell models, in combination with different genetic perturbations. This will allow us to place the second messengers into their cellular context. Ultimately, this research will highlight new drug targets and can thus be exploited for the design of novel therapeutics.
Conway JH, Fiedler D. (2015) An affinity reagent for the recognition of pyrophosphorylated peptides. Angew Chem Int Ed Engl. 54:3941-5. Pubmed
Yates LM, Fiedler D. (2015) Establishing the stability and reversibility of protein pyrophosphorylation with synthetic peptides. Chembiochem. 16:415-23. Pubmed
Wu M, Chong LS, Capolicchio S, Jessen HJ, Resnick AC, Fiedler D. (2014) Elucidating diphosphoinositol polyphosphate function with nonhydrolyzable analogues. Angew Chem Int Ed Engl. 53: 7192-97. Pubmed
Kliegman JI, Fiedler D, Ryan CJ...Shokat KM. (2013) Chemical genetics of rapamycin-insensitive TORC2 in S. cerevisiae. Cell Rep. 5: 1725-36. Pubmed
Marmelstein AM, Yates LM, Conway JH, Fiedler D. (2013) Chemical pyrophosphorylation of functionally diverse peptides. J Am Chem Soc. 136: 108-11. Pubmed
Wu M, Dul BE, Trevisan AJ, Fiedler D. (2013) Synthesis and characterization of non-hydrolysable diphosphoinositol polyphosphate second messengers. Chem Sci. 4: 405-10. Pubmed
Nakamura JL, Phong C, Pinarbasi E,...Fiedler D,...Shannon K. (2011) Dose-dependent effects of focal fractionated irradiation on secondary malignant neoplasms in Nf1 mutant mice. Cancer Res. 71: 106-15. Pubmed
van Wageningen S, Kemmeren P, Lijnzaad P,...Fiedler D,...Holstege FC. (2010) Functional overlap and regulatory links shape genetic interactions between signaling pathways. Cell. 143: 991-1004. Pubmed
Bandyopadhyay S, Mehta M, Kuo D,...Fiedler D,...Ideker T. (2010) Rewiring of genetic networks in response to DNA damage. Science. 330: 1385-89. Pubmed
Beltrao P, Trinidad JC, Fiedler D,...Krogan NJ. (2009) Evolution of phosphoregulation: comparison of phosphorylation patterns across yeast species. PLoS Biol. 7: e1000134. Pubmed
Fiedler D, Braberg H, Mehta M,...Krogan NJ. (2009) Functional organization of the S. cerevisiae phosphorylation network. Cell. 136: 952-63. PubMed
Okuzumi T, Fiedler D, Zhang C,...Shokat KM. (2009) Inhibitor hijacking of Akt activation. Nat Chem Biol. 5: 484-93. PubMed
Davis AV, Fiedler D, Ziegler M, Terpin A, Raymond KN. (2007) Resolution of chiral, tetrahedral M4L6 metal-ligand hosts. J Am Chem Soc. 129: 15354-63. PubMed
Fiedler D, van Halbeek H, Bergman RG, Raymond KN. (2006) Supramolecular catalysis of unimolecular rearrangements: substrate scope and mechanistic insights. J Am Chem Soc. 128: 10240-52. PubMed
Fiedler D, Bergman RG, Raymond KN. (2006) Stabilization of reactive organometallic intermediates inside a self-assembled nanoscale host. Angew Chem Int Ed Engl. 45: 745-48. PubMed
Fiedler D, Bergman RG, Raymond KN. (2004) Supramolecular catalysis of a unimolecular transformation: aza-Cope rearrangement within a self-assembled host. Angew Chem Int Ed Engl. 43: 6748-51. PubMed
Fiedler D, Leung DH, Bergman RG, Raymond KN. (2004) Enantioselective guest binding and dynamic resolution of cationic ruthenium complexes by a chiral metal-ligand assembly. J Am Chem Soc. 44: 1000-02.