Faculty

Stephen W. Ragsdale

Professor of Biological Chemistry

Ph.D., University of Georgia
Postdoctoral Fellow, Case Western Reserve University

Research Focus: Enzyme Mechanisms; Metals in Biology; Redox Regulation

Phone: 734.615.4621
Fax: 734.763.4581
E-mail: sragsdal@umich.edu

My laboratory studies processes that are important in energy and the global carbon cycle and in regulation of metabolism by metals and gas signaling molecules. Our work is at the interfaces among chemistry, biology, and physics in using a variety of molecular, chemical and biophysical approaches to understand these processes. Our research is funded by the National Institutes of Health and the Department of Energy.

Microbial CO2, CO and Methane Metabolism: We are trying to understand how microbes make methane, the key component of natural gas. We use kinetics, spectroscopy, structural methods and molecular genetics to elucidate the steps and capture the intermediates involved in methanogenesis and in the anaerobic oxidation of methane. Much of our attention focuses on methyl coenzyme M reductase (MCR), which contains a nickel tetrapyrrolic cofactor and is responsible for all biologically generated methane. Based on recent studies in which we trapped intermediates in the MCR reaction mechanism and characterized them by spectroscopic and crystallographic methods, we proposed a novel mechanism for methane synthesis involving novel metal-based and radical intermediates.

Microbial CO2, CO and Mercury Metabolism: One of the key processes that underlies all life on earth is the global carbon cycle. We are characterizing the key enzymes involved in an unusual pathway of CO2 fixation. This work is uncovering novel types of metal centers that rapidly and efficiently catalyze challenging reactions (like reduction of CO2), new ways that substrates are directed to enzyme active sites (CODH/ACS contains a 70 Å tunnel between active sites), and intriguing ways that enzymes interact and move during catalysis. We also are studying the enzymatic system involved in microbial methyl-mercury production.  

Oxygen Sensing and Thiol-Disulfide Regulation: We have discovered a mode of metabolic regulation in which thiol/disulfide redox switches control the function of diverse proteins through regulating their affinity for heme.  We identified and characterized a redox switch in human heme oxygenase-2 (HO2), which plays an important role in heme homeostasis and in generating CO, a signal molecule that regulates many physiological processess. We also have recently uncovered a thiol/disulfide redox switch that regulates heme binding to regulate heme oxygenase and a transcriptional regulator that regulates a variety of metabolic processes (lipid and glucose metabolism, inflammation and the circadian rhythm).

 

 

Awards

2009
Frederick J. Bollum Endowed Biochemistry Lectureship, University of Minnesota
2009
Ljungdahl Lectureship, University of Georgia, Athens, GA
2009 Fellow of the American Association for the Advance of Science
2006 Elected Fellow of the American Academy of Microbiology
2003 Outstanding Research and Creativity Award from the University of Nebraska System
2003 Charles E. Bessey Professorship
1987-1992 Shaw Scholar Award, Milwaukee Foundation

 

Representative Publications

  1. Cedervall, P.E., Dey, M., Li, X., Sarangi, R, Hedman, Ragsdale, S.W., and *Wilmot, C.M. (2011) Structural analysis of a Ni-methyl species in methyl-coenzyme M reductase from Methanothemobacter marburgensis, Journal of the American Chemical Society, 133: 5626-8. Faculty of 1000 Pick. PMC3086036.

  2. Gupta, N. & Ragsdale, S.W. (2011) Thiol-Based Redox Regulation of Heme Binding to Rev-erbβ, a Human Transcriptional Regulator of the Circadian Cycle, Journal of Biological Chemistry. 286: 4392-4403. PMC3039370

  3. Pierce, E., Becker, D.F., and Ragsdale, S.W. (2010) Identification and Characterization of Oxalate Oxidoreductase, a Novel Thiamine Pyrophosphate-dependent 2-Oxoacid Oxidoreductase that Enables Anaerobic Growth on Oxalate, Journal of Biological Chemistry 285: 40515-40524. PMC3003350.

  4. Dey, M., Xi, X., Kunz, R. C., and Ragsdale, S. W. (2010) Detection of Organometallic and Radical Intermediates in the Catalytic Mechanism of Methyl-Coenzyme M Reductase Using the Natural Substrate Methyl-Coenzyme M and a Coenzyme B Substrate Analog, Biochem. 49: 10902-10911. PMID: 21090696

  5. Bender, G., Stich, T.A., Yan, L., Britt, R.D., Cramer, S.P., and Ragsdale, S.W. (2010) Probing the catalytic mechanism of acetyl-CoA synthase by infrared and EPR characterization of the photolyzed Ni(I)-CO intermediate, Biochemistry 49:  7516–7523. Faculty of 1000 Pick. PMC2932805.

  6. Yi, L., Morgan, J.T., and Ragsdale, S.W. (2010) Identification of a thiol/disulfide redox switch in the human BK channel that controls its affinity for heme and CO, Journal of Biological Chemistry 284: 20556-20561. PMC2742820.

  7. Woolerton, T.W., Sheard, S., Reisner, E., Pierce, E., Ragsdale, S.W., and *Armstrong, F.A. (2010) Efficient and clean photo-reduction of CO2 to CO by enzyme-modified TiO2 nanoparticles using visible light, Journal of the American Chemical Society 132: 2132–2133. PMC2845288.

     

PubMed Search Term:

Ragsdale SW

 

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