Areas of Interest
Our laboratory is interested in enzymology and protein design. Our research is inherently inter-disciplinary in nature and draws on a synergistic combination of bio-organic, bio-inorganic and bio-physical chemistry. We are fortunate to enjoy various productive collaborations with other research groups at Michigan.
Our interest in protein design led us to explore the properties of novel "Teflon-like" proteins that incorporate highly fluorinated amino acids within their hydrophobic cores. We have designed a series of model proteins that contain the fluorinated amino acid hexafluoroleucine to examine how fluorination can be used to modulate the physical and biological properties of proteins. We found that fluorinated proteins exhibit remarkable stability that allows them to resist unfolding by heat and organic solvents and degradation by proteases. We are applying these design principles to the development of fluorinated antimicrobial peptides, short peptides that kill bacteria by selectively disrupting their membranes. We aim to design fluorous antimicrobial peptides that will have enhanced selectivity for bacterial membranes and better resist degradation by proteases. We are also developing methods to follow the fate of peptides in vivo using fluorine NMR as a probe.
We are currently studying three enzymes that catalyze unusual and chemically difficult reactions that involve metal cofactors and/or reactive free radical intermediates. Benzylsuccinate synthase is a free radical-containing enzyme that catalyzes the first step in the metabolism of toluene - anaerobic bacteria that contain this enzyme can live on toluene as their sole carbon source! Glutamate mutase catalyzes an unusual carbon skeleton rearrangement involved in glutamate fermentation; it uses coenzyme B12, a cobalt-containing organo-metallic complex, to generate reactive free radicals that initiate the reaction mechanism. Lastly, we have begun to study aldehyde decarbonylase, an enzyme that catalyzes the conversion of long-chain aldehydes to alkanes and carbon monoxide, which is involved in hydrocarbon biosynthesis in plants and algae.
Increasingly, our attention is focused on enzymes involved in hydrocarbon metabolism as these may prove useful for the synthesis of new biofuels and bioremediation of hydrocarbon-contaminated soils. Our primary goal is to understand how these enzymes generate and control chemically reactive intermediates to catalyze their reactions; we then aim to apply what we learn to engineer new pathways for hydrocarbon metabolism.
Honors & Awards
Doctor of Science, University of Cambridge, 2007
Fellow, Royal Society of Chemistry, U.K., 2005
Co-Chair, Bioorganic Chemistry Gordon Research Conference, 2005
G.W. Raiziss Distinguished Visiting Fellow, University of Pennsylvania, 2001
Research Fellow, Darwin College, University of Cambridge, 1992
Royal Society University Research Fellowship, 1990
Viperin: an ancient radical-SAM enzyme finds its place in modern cellular metabolism and innate immunity.
Ghosh S, Marsh ENG.
J Biol Chem. 2020; 295: 11513–28.
Targeting viperin to the mitochondrion inhibits the thiolase activity of the trifunctional enzyme complex.
Dumbrepatil AB, Zegalia KA, Sajja K, Kennedy RT, Marsh ENG.
J Biol Chem. 2020; 295: 2839–49.
Interactions between Viperin, Vesicle-associated Membrane Protein A and Hepatitis C Virus Protein NS5A Modulate Viperin Activity and NS5A Degradation.
Ghosh S, Patel AM, Grunkemeyer TJ, Dumbrepatil AB, Zegalia KA, Kennedy RT, Marsh ENG.
Biochemistry. 2020; 59: 780–9.
Probing Metal Ion Discrimination in a Protein Designed to Bind Uranyl Cation With Femtomolar Affinity.
Hoarau M, Koebke KJ, Chen Z, Marsh ENG.
Front Mol Biosci. 2019; 6: 73.
Metal-Dependent Assembly of a Protein Nano-Cage.
Cristie-David AS, Marsh ENG.
Protein Sci. 2019; 28: 1620–9.
Coiled-Coil-Mediated Assembly of an Icosahedral Protein Cage with Extremely High Thermal and Chemical Stability.
Cristie-David AS, Chen J, Nowak DB, Bondy AL, Sun K, Park SI, Banaszak Holl MM, Su M, Marsh ENG.
J Am Chem Soc. 2019; 141: 9207–16.
Viperin interacts with the kinase IRAK1 and the E3 ubiquitin ligase TRAF6, coupling innate immune signaling to antiviral ribonucleotide synthesis.
Dumbrepatil AB, Ghosh S, Zegalia KA, Malec PA, Hoff JD, Kennedy RT, Marsh ENG.
J Biol Chem. 2019; 294: 6888–98.
For a list of publications from PubMed, click HERE