Stephen W. Ragsdale, Ph.D.

Professor, Biological Chemistry

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

Research Profile

Our research at the chemistry-biology interface is aimed at understanding how organisms utilize gases (carbon monoxide, carbon dioxide, methane) in metabolism and in metabolic regulation. We also are studying how metals are involved in catalysis by some important metalloenzymes (e.g., nickel-, iron-sulfur-, heme-, and B12-proteins) and in regulation of metabolic processes. A third interrelated project is the role of thiol/disulfide redox chemistry in regulation of enzyme function and transcription. We are studying these broad areas in some specific microbial and human systems that are important in human health, environmental biology, and biological energy conversion.

We are studying human heme oxygenase-2 (HO-2), which plays a major cellular role in heme homeostasis and is the only known source of CO in mammals. CO (toxic at high levels) is a signal molecule that is linked to the regulation of many physiological processes, including oxygen sensing, circadian rhythm, and olfactory sensing. Similarly, heme is an essential cofactor that is toxic at elevated concentrations and plays an important role in metabolic regulation. We recently determined the first crystal structure of HO-2 in collaboration with George Phillips (U. Wisconsin) and uncovered a thiol/disulfide redox switch that regulates heme binding. We are evaluating the role of this redox switch in the function of HO-2 and of a related switch in its physiological partners, including a potassium channel and transcriptional regulators involved in the circadian cycle.

We are studying microbial processes that are important in environmental biology and biological energy conversion, such as the microbial metabolism of greenhouse and energy-rich gases (carbon dioxide, carbon monoxide, methane). Other projects aim at generating enzyme-linked fuel cells and engineering organisms for biofuel and chemical production. In one project, we are studying the mechanism of methyl coenzyme M reductase, which contains a nickel tetrapyrrole and is responsible for all biologically generated methane. We also are studying a macromolecular machine, a nickel-iron-sulfur enzyme called CO dehydrogenase/acetyl-CoA synthase, which enables microbial growth on CO2 and CO, by a novel pathway of anaerobic acetyl-CoA synthesis. This enzyme complex contains a 140 angstrom channel through which CO migrates during catalysis. In addition, we are studying methyl and proton transfer in a methyltransferase and a vitamin B12/iron-sulfur protein, and characterizing how enzymes use radical intermediates in catalysis.

Awards

1987-92 Shaw Scholar Award, Milwaukee Foundation
2003 Outstanding Research and Creativity Award from the Univ. Nebraska System
2003 Charles E. Bessey Professorship
2006 Elected Fellow of the American Academy of Microbiology

PubMed Search Term : Ragsdale+sw[au

Selected Publications

2009:
Lazarus, O., Woolerton, T., Parkin, A., Lukey, M., Reisner, E., Seravalli, J., Pierce, E., Ragsdale, S.W., Sargent, F. & Armstrong, F. (2009) Water-Gas Shift Reaction Catalyzed by Redox Enzymes on Conducting Graphite Platelets, Journal of the American Chemical Society 48: in press.

Kung, Y., Doukov, T.I., Seravalli, J., Ragsdale, S.W., Drennan, C.L. (2009) Crystallographic snapshots of cyanide- and water-bound C-clusters from bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase, Biochemistry 48: 7432-7440.

Dey, M., Li, X., Zhou, Y., and Ragsdale, S.W. (2009) Evidence for Organometallic Intermediates in Bacterial Methane Formation Involving the Nickel Coenzyme F430, In Metal Ions in Life Sciences, Vol. 7. Sigel, A. & H. Sigel, Eds. Royal Society of Chemistry. Cambridge, UK., in press.

Ragsdale, S.W. (2009) Nickel-based enzymatic systems Journal of Biological Chemistry 284: 18571-18575.

Yi, L., Jenkins, P. M., Leichert, L. I., Jakob, U., Martens, J. R., and Ragsdale, S.W. (2009) The heme regulatory motifs in heme oxygenase-2 form a thiol/disulfide redox switch that responds to the cellular redox state, Journal of Biological Chemistry 284: 20556-20561.

Sarangi, R., Dey, M., and Ragsdale, S.W. (2009) Geometric and Electronic Structures of the Ni(I) and Methyl-Ni(III) Intermediates of Methyl-Coenzyme M Reductase, Biochemistry 48: 3146-3156.

2008:
Ragsdale, S.W. and Pierce, E. (2008) Acetogenesis and the Wood-Ljungdahl Pathway of CO2 Fixation, Biochimica et Biophysica Acta - Proteins and Proteomics 283: 1873-1898

Gupta, N. and Ragsdale, S.W. (2008) Dual roles of an essential cysteine residue in activity of a redox-regulated bacterial transcriptional activator, Journal of Biological Chemistry 283: 28721-28728.

Pierce, E., Xie, G., Barabote, R. D., Saunders, E., Han, C. S., Detter, J. C., Richardson, P., Brettin, T. S., Das, A., Ljungdahl, L. G., and Ragsdale, S.W. (2008) The Complete Genome Sequence of Moorella thermoacetica, Environmental Microbiology 10: 2550-2573.

Seravalli, J. and Ragsdale, S.W. (2008) 13C-NMR characterization of an exchange reaction between CO and CO2 catalyzed by carbon monoxide dehydrogenase, Biochemistry 47: 6770-6781. Faculty of 1000 Pick

Seravalli, J and Ragsdale, S.W. (2008) Pulse-chase studies of the synthesis of acetyl-coenzyme A by carbon monoxide dehydrogenase/acetyl-CoA synthase: Evidence for a random mechanism of methyl and CO addition, Journal of Biological Chemistry 283: 8384-8394.

Doukov, T.I., Blasiak, L.C., Seravalli, J., Ragsdale, S.W., and Drennan, C.L. (2008) Xenon in and at the end of the tunnel of bifunctional Carbon Monoxide Dehydrogenase/Acetyl-CoA Synthase Biochemistry 47: 3474-3483.

Kunz, R. C., Dey, M., and Ragsdale, S.W. (2008) Characterization of the Thioether Product Formed From the Thiolytic Cleavage of the Alkyl-Nickel Bond in Methyl-Coenzyme M Reductase Biochemistry 47: 2661-2667.

2007:
Ragsdale, S.W. (2007) Nickel and the Carbon Cycle. Journal of Inorganic Biochemistry 101: 1657–66.

Bianchetti C. M., Li, Y., Ragsdale, S.W., and Phillips, G.N., Jr. (2007) Comparison of Apo and Heme-bound Crystal Structures of a Truncated Human Heme Oxygenase-2, Journal of Biological Chemistry 282: 37624-37631.

Dey M, Telser, J, Kunz R.C., Lees, N.S., Ragsdale, S.W., Hoffman, B. (2007) Biochemical and spectroscopic studies of the electronic structure and reactivity of a methyl-Ni species formed on Methyl-Coenzyme M Reductase, Journal of the American Chemical Society 129: 11030-2. Faculty of 1000 Pick

Yi, Li and Ragsdale, S.W. (2007) Evidence that the heme regulatory motifs in heme oxygenase-2 serve as a thiol/disulfide redox switch regulating heme binding. Journal of Biological Chemistry, 282: 21056-21067.

Doukov, T.I., Hemmi, H., Drennan, C.L., and Ragsdale, S.W. (2007) Structural And Kinetic Evidence For An Extended Hydrogen Bonding Network In Catalysis Of Methyl Group Transfer: Role Of An Active Site Asparagine Residue In Activation Of Methyl Transfer By Methyltransferases, Journal of Biological Chemistry 282: 6609-6618. Paper of the week, Faculty of 1000 Pick.