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Heather R. Lucas

Education

B.S., Randolph-Macon College, 2002

Ph.D., Johns Hopkins University, 2009

Visiting Fellow, Global Center of Excellence, Osaka University, 2008

Lenfant Biomedical Fellow, National Heart, Lung, and Blood Institute, 2008-2011

NIH Postdoctoral Fellow, National Institute on Aging, 2011-2013

Honors and Awards

2011                            Lenfant Biomedical Award, National Heart, Lung, and Blood Institute

2009                            Young Investigator Award, American Chemical Society

2006 – 2007                Zeltmann Fellowship in Chemistry, Johns Hopkins University

2006                            Gordon Research Seminar Chair’s Fund Award, Bioinorganic Chemistry

2002                            The American Institute of Chemists Award, Randolph-Macon College

Research Interests

The focus of the Lucas research group encompasses inorganic biochemistry, bioinorganic synthesis, chemical biology, and biophysics.  Research opportunities are available at the postdoctoral, graduate, and undergraduate levels.  Email requests for more information are welcomed!

Physiological Metal Imbalance, Neurodegeneration, and Aging

Oxidatively modified or inactive proteins accumulate during normal aging and under pathological conditions.  In recent years, research has established that biometals are elevated in aging populations, contributing to the generation of free radicals and enhanced oxidative and/or nitrosative stress.  Exogenous metal can promote protein aggregation as a result of metal-mediated generation of reactive oxygen species (ROS) or reactive nitrogen species (RNS), leading to protein modification, altered DNA repair mechanisms, and/or cell damage. Through the exploitation of chemical and biological techniques, the role of metal dyshomeostasis on aging and disease onset is under investigation.  Emphasis is placed on proteins associated with diseases such as Alzheimer’s disease, Parkinson’s disease, Werner syndrome, and other premature aging diseases.  Overall, discoveries from this project will aid in elucidating the precise mechanisms by which a physiological metal imbalance contributes to neurotoxicity. Through this knowledge, new strategies for intervention could lead to earlier diagnosis and increased lifespan.

Rational Design of Light-Initiated Metallodrugs

Transition metal complexes attract attention due to their innate ability to mediate cellular signaling pathways as well as facilitate both NO and O2 transformations. In cancer therapeutics, metal-based photosensitizers have long been used for their ability to produce reactive oxygen species (ROS) at targeted tumor sites upon illumination.  Likewise, NO and CO donating drugs have been employed in photodynamic therapy as agents for cancer treatment and cardiovascular control.  The aim of this project is to design, synthesize, and characterize new ligand-metal complexes that achieve O2, NO, and CO photodissociation. Variable temperature transient absorbance laser flash photolysis is employed to measure the kinetic and thermodynamic properties that govern small molecule binding and release from these novel metallocomplexes.  Knowledge gained through this project will offer a systematic approach towards the development of a new generation of photoactivated metallodrugs, highlighting ligand/metal tunability as a key strategy for biomedical applications.

Contribution of Transition Metals to Olfaction

Significant loss in olfactory functioning (anosmia) is known to occur with aging and has been attributed to a variety of factors including physiological changes, environmental factors, and disease. Within the literature, toxicology studies have shown that transition metals can be incorporated into neuronal cells from the nasal cavity, stimulating neurodegeneration and the loss of smell.  Miscompartmentalization of exogenous metal in the brain could also initiate an imbalance of biometals that are important for healthy cellular functions.  In order to gain a molecular level understanding of metal coordination to olfactory receptors, peptide models will be designed and characterized.  The ability of metal bound peptide to incorporate into synthetic membranes upon odorant binding will also be explored.  Research in this area may provide insight into the link between olfaction and neurodegeneration.

Book Chapters

Lucas, H. R.; Lee, J. C.; Emerging Role for Copper-Bound α-Synuclein in Parkinson’s Disease Etiology. In Brain Diseases and Metalloproteins; D. R. Brown, Ed.; Pan Stanford, 2013, pp 295-316.

Lucas, H. R.; Karlin, K. D.; Copper-Carbon Bonds in Mechanistic and Structural Probing of Proteins as well as in Situations where Copper is a Catalytic or Receptor Site. In Metal-Carbon Bonds in Enzymes and Cofactors; Sigel, A., Sigel, H., Sigel, R. K. O., Eds.; Metal Ions in Life Sciences Vol. 6; The Royal Society of Chemistry: Cambridge, UK, 2009, pp 295-362.

Representative Publications

Lucas, H. R.; Rifkind, J. M. Considering the Vascular Hypothesis of Alzheimer’s Disease: Effect of Copper Associated Amyloid on Red Blood Cells.  Adv. Exp. Med. Biol. 2013, 765, 131-8.

Lucas, H. R.; Lee, J. C. Copper(II) enhances membrane-bound α-synuclein helix formation.  Metallomics 2011, 3, 280-3.  Cover Article: Special Thematic Issue on Metals and Neurodegenerative Diseases

Lucas, H. R.; DeBeer, S.; Hong, M. S.; Lee, J. C. Evidence for Copper-Dioxygen Reactivity during α-Synuclein Fibril Formation.   J. Am. Chem. Soc. 2010, 132, 6636-7.

Lucas, H. R.; Lee, J. C. Effect of Dioxygen on Copper(II) Binding to α-Synuclein.  J. Inorg. Biochem. 2010, 104, 245-9.

Fukuzumi, S.; Kotani, H.; Lucas, H. R.; Doi, K.; Suenobu, T.; Peterson, R. L.; Karlin, K. D. Mononuclear Copper Complex Catalyzed Four-Electron Reduction of Oxygen.  J. Am. Chem. Soc. 2010, 132, 6874-5.

Lucas, H. R.; Meyer, G. J.; Karlin, K. D. CO and O2 Binding to Pseudo-Tetradentate Ligand-Copper(I)-Complexes with a Variable N-Donor Moiety:  Kinetic/ Thermodynamic Investigation Reveals Ligand Induced Changes in Reaction Mechanism.  J. Am. Chem. Soc. 2010, 132, 12927-40.

Lee, Y.; Lee, D.-H.; Park, G. Y.; Lucas, H. R.; Sarjeant, A. A. N.; Keiber-Emmons, M. T.; Vance, M. A.; Milligan, A. E.; Solomon, E. I.; Karlin, K. D. Sulfur Donor Atom Effects on Copper(I)/O2 Chemistry with Thioanisole Containing Tetradentate N3S Ligand Leading to μ-1,2-Peroxo-Dicopper(II) Species.  Inorg. Chem. 2010, 49, 8873-85.

Woertink, J. S.; Tian, L.; Maiti, D.; Lucas, H. R.; Himes, R. A.; Karlin, K. D.; Neese, F.; Würtele, C.; Holthausen, M.; Bill, E.; Sundermeyer, J.; Schindler, S.; Solomon, E. I. Spectroscopic and Computational Studies of an End-on Bound Superoxo-Cu(II) Complex: Geometric and Electronic Factors that Determine the Ground State. Inorg. Chem. 2010, 49, 9450-9.

Lucas, H. R.; Meyer, G. J.; Karlin, K. D.  CO and NO Ligand Dynamics in Synthetic Heme and Heme-Copper Complex Systems.  J. Am. Chem. Soc. 2009, 131, 13924-5.  Highlighted in JACSb Select issue #10: “The Interface of Inorganic Chemistry and Biology”

Lucas, H. R.; Li, L.; Sarjeant, A. A. N.; Vance, M. A.; Solomon, E. I.; Karlin, K. D.  Toluene and Ethylbenzene Aliphatic C-H Bond Oxidations Initiated by a  m-1,2-Peroxodicopper(II) Complex.   J. Am. Chem. Soc. 2009, 131, 3230-45.   

Lee, Y.; Park, G.Y.; Lucas, H. R.; Vajda, P. L.; Kamaraj, K.; Vance, M. A.; Milligan, A. E.; Woertink, J. S.; Siegler, M. A.; Sarjeant, A. A. N.; Zakharov, L. N.; Rheingold, A. L.; Solomon, E. I.; Karlin, K. D.  CuI/O2 Chemistry with Imidazole Containing Tripodal Tetradentate Ligands Leading to a μ-1,2-Peroxo-Dicopper(II) Species.  Inorg. Chem. 2009, 48, 11297-11309.

Fry, H. C.; Lucas, H. R.; Sarjeant, A. A. N.; Meyer, G. J.; Karlin, K. D.  Carbon Monoxide Coordination and Photodissociation in Copper(I) Polypyridine Compounds.  Inorg. Chem. 2008, 47, 241-56.

Fry, H. C.; Lucas, H. R.; Sarjeant, A. A. N.; Meyer, G. J.; Karlin, K. D.  Inter- vs. Intramolecular Electron-/Atom- Transfer in Heme-Iron and Copper Pyridylalkylamine Complexes.  Inorg. Chim. Acta 2008, 361, 1100-1115.   Special Issue in Honor of Edward I. Solomon (Stanford University)

Maiti, D.; Lucas, H. R.; Sarjeant, A. A. N.; Karlin, K. D. Aryl Hydroxylation by a Mononuclear Copper-Hydroperoxo Species.  J. Am. Chem. Soc. 2007, 129, 6998-9.