The innate immune system provides plants and mammals with non-specific and front-line defense mechanisms following invasion by microbial pathogens. In broad terms, our initiatives in this area address the structures, reaction mechanisms, and physiological functions of putative metalloproteins and –peptides that are components of the mammalian innate immune response. Our aim is to understand how and why certain broad-range antimicrobial peptides co-exist with and/or utilize d-block metal ion stores. Ultimately, these studies will provide new insights into metal ion physiology, host/pathogen interactions and microbial pathogenesis, and may guide the design of new small-molecule antimicrobial agents.
Many species of Gram-negative bacteria biosynthesize and posttranslationally modify ribosomal peptides that exhibit potent antimicrobial activity. The producer organism must be immune to the antibiotic it biosynthesizes and exports; in some cases, immunity peptides provide protection. Often, the mechanisms of action of these peptides are unclear. We seek to decipher how immunity peptides, encoded by gene clusters responsible for the biosynthesis of antibiotics that utilize metal ion transporters to enter target bacterial cells, protect the producer organism. We also aim to employ the enzymes responsible for posttranslational modification of such ribosomal peptide scaffolds in the chemoenzymatic synthesis of novel small-molecule and peptide-based antibiotics directed to Gram-negative strains.
Metalloproteins and –peptides such as superoxide dismutase, metallothionein, and tyrosine hydroxylase play critical roles in neurobiology. Failures of metal ion homeostasis and metalloprotein misfolding have been correlated to many neurodegenerative diseases. For instance, ~100 single point mutations in CuZn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral schlerosis (ALS), a genetic disease that affects motor neurons. We are interested in ascertaining how a neuronal cell transports, processes and attempts to clear SOD1 point mutants. We will interrogate a putative adaptor function of a zinc-containing protein that would allow transport of mSOD1 along the microtubule network. Correlations of mSOD1 trafficking with disease prognosis should provide new insights into the pathophysiology of familial ALS and protein aggregation, which is a pathological hallmark of neurodegenerative diseases.
Our experimental approach blends the techniques of inorganic and organic chemistries, biochemistry, enzymology, and cell biology. Students and post-doctoral researchers will have the opportunity to gain expertise in synthesis, molecular biology, protein/peptide overexpression/synthesis and purification, mechanistic enzymology, coordination chemistry and spectroscopy (UV-Vis, CD, NMR, EPR, etc.), prokaryotic and eukaryotic cell culture, and fluorescence microscopy.
Elisa Tomat, Elizabeth M. Nolan, Jacek Jaworski and Stephen J. Lippard, “Organelle-Specific Zinc Detection Using Zinpyr-Labeled Fusion Proteins in Live Cells,” J. Am. Chem. Soc. 2008, 130, 15776-15777.
Elizabeth M. Nolan and Christopher T. Walsh, “Investigations of the MceIJ-Catalyzed Posttranslational Modification of the Microcin E492 C-Terminus: Linkage of Ribosomal and Nonribosomal Peptides to Form ‘Trojan Horse’ Antibiotics,” Biochemistry 2008, 47, 9289-9299.
Rebecca F. Roush, Elizabeth M. Nolan, Frank Löhr and Christopher T. Walsh, “Maturation of an Escherichia coli Ribosomal Peptide by ATP-Consuming N—P Bond Formation,” J. Am. Chem. Soc. 2008, 130, 3603-3609.
Elizabeth M. Nolan, Michael A. Fischbach, Alexander Koglin and Christopher T. Walsh, “Biosynthetic Tailoring of Microcin E492m: Post-Translational Modification Affords an Antibacterial Siderophore-Peptide Conjugate,” J. Am. Chem. Soc. 2007, 129, 14336-14347.
Michael L. Neidig, Christina D. Brown, Ken Light, Danica Galonic Fujimori, Elizabeth M. Nolan, John C. Price, Eric W. Barr, J. Martin Bollinger, Jr., Carsten Krebs, Christopher T. Walsh and Edward I. Solomon, “CD and MCD of CytC3 and Taurine Dioxygenase: Role of the Facial Triad in α-KG-Dependent Oxygenases,” J. Am. Chem. Soc. 2007, 129, 14224-14231.
Elizabeth M. Nolan and Stephen J. Lippard, “Turn-On and Ratiometric Mercury Sensing in Water with a Red-Emitting Probe,” J. Am. Chem. Soc. 2007, 129, 5910-5918.
Elizabeth M. Nolan, Jubin W. Ryu, Jacek Jaworski, Rodney P. Feazell, Morgan Sheng and Stephen J. Lippard, “Zinspy Sensors with Enhanced Dynamic Range: Imaging Neuronal Cell Zinc Uptake and Mobilization,” J. Am. Chem. Soc. 2006, 128, 15517-15528.
Elizabeth M. Nolan, Jacek Jaworski, Maryann E. Racine, Morgan Sheng and Stephen J. Lippard, “Moderate Affinity Fluorescent Zinc Sensors of the Zinpyr Family: Syntheses, Characterization and Biological Imaging Applications,” Inorg. Chem. 2006, 45, 9748-9757.
Elizabeth M. Nolan, Maryann E. Racine and Stephen J. Lippard, “Selective Hg(II) Detection in Aqueous Solution with Thiol Derivatized Fluoresceins,” Inorg. Chem. 2006, 45, 2742-2749.
Elizabeth M. Nolan, Jacek Jaworski, Ken-Ichi Okamoto, Yasunori Hayashi, Morgan Sheng and Stephen J. Lippard, “QZ1 and QZ2: Rapid, Reversible Quinoline-Derivatized Fluoresceins for Sensing Biological Zn(II),” J. Am. Chem. Soc. 2005, 127, 16812-16823.
Christopher J. Chang, Elizabeth M. Nolan, Jacek Jaworski, Ken-Ichi Okamoto, Yasunori Hayashi, Morgan Sheng and Stephen J. Lippard, “ZP8, a Neuronal Zinc Sensor with Improved Dynamic Range; Imagining Zinc in Hippocampal Slices with Two-Photon Microscopy,” Inorg. Chem. 2004, 43, 6774-6779.
Elizabeth M. Nolan, Shawn C. Burdette, Jessica J. Harvey, Scott A. Hilderbrand and Stephen J. Lippard, “Synthesis and Characterization of Zinc Sensors Based on a Monosubstituted Fluorescein Platform,” Inorg. Chem. 2004, 43, 2624-2635.
Christopher J. Chang, Elizabeth M. Nolan, Jacek Jaworski, Shawn C. Burdette, Morgan Sheng and Stephen J. Lippard, “Bright Fluorescent Chemosensor Platforms for Imaging Endogenous Pools of Neuronal Zinc,” Chem. Biol. 2004, 11, 203-210.
Christopher J. Chang, Jacek Jaworski, Elizabeth M. Nolan, Morgan Sheng and Stephen J. Lippard, “A tautomeric zinc sensor for ratiometric fluorescence imaging: application to nitric oxide-induced release of intracellular zinc,” Proc. Natl. Acad. Sci. USA 2004, 101, 1129-1134.
Elizabeth M. Nolan and Stephen J. Lippard, “A ‘Turn-On’ Fluorescent Sensor for the Selective Detection of Mercuric Ion in Aqueous Media,” J. Am. Chem. Soc. 2003, 125, 14270-14271 (highlighted in Thomson ESI Special Topics, June 2005).
Elizabeth M. Nolan and R. G. Linck, “Through Space Charge and Dipolar Effects in Substituted Ethanes and 1,1,1-Trifluoroethanes,” J. Phys. Chem. A. 2002, 106, 533-543.
Elizabeth M. Nolan and R. G. Linck, “An Exploration of Long Range Electronic Effects in Substituted Alkanes,” J. Phys. Chem. A. 2001, 105, 7297-7307.
Elizabeth M. Nolan and R. G. Linck, “Charges in Substituted Alkanes: Evidence for a Through Space Mechanism,” J. Am. Chem. Soc. 2000, 122, 11497-11506.
Reviews and Commentaries
Elizabeth M. Nolan and Christopher T. Walsh, “Chemical Biology and Natural Product Discovery” (commentary), ChemBioChem, 2009, 10, 24-25.
Elizabeth M. Nolan and Christopher T. Walsh, “How Nature Morphs Peptide Scaffolds into Antibiotics” (review), ChemBioChem, 2009, 10, 34-53.
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