# Stephen W. Ragsdale
**Stephen W. Ragsdale** (also published as Stephen Ragsdale and S. W. Ragsdale) is an American biological chemist who studies how microbes use nickel-containing enzymes to metabolize one-carbon compounds such as carbon monoxide, carbon dioxide, and methane. He is the David Ballou Collegiate Professor of Biological Chemistry and a Professor of Biological Chemistry at the University of Michigan, where his laboratory works on the mechanisms of nickel, B12, heme, and iron-sulfur enzymes and on the regulation of metabolism by heme, carbon monoxide, and thiol-disulfide redox switches.[1](https://ies.engin.umich.edu/profile/ragsdale-stephen/) He is known chiefly for his work on two nickel enzyme systems: CO dehydrogenase/acetyl-CoA synthase, the central enzyme of the [Wood–Ljungdahl pathway](https://www.edgepedia.org/wood-ljungdahl-pathway) of anaerobic carbon dioxide fixation, and methyl-coenzyme M reductase, the enzyme responsible for nearly all biologically generated methane.[1](https://ies.engin.umich.edu/profile/ragsdale-stephen/)
| Key facts | |
|---|---|
| Position | David Ballou Collegiate Professor of Biological Chemistry, University of Michigan[1](https://ies.engin.umich.edu/profile/ragsdale-stephen/) |
| Field | Biological chemistry of nickel enzymes and one-carbon metabolism[1](https://ies.engin.umich.edu/profile/ragsdale-stephen/) |
| Career | Assistant Professor, University of Wisconsin–Milwaukee; Associate through Full Professor and named chair, University of Nebraska; Professor at Michigan since 2007[2](https://cse.umn.edu/chem/events/professor-steve-ragsdale) • [3](https://www.linkedin.com/in/stephen-ragsdale-93544721) |
| Signature work | 2016 Science paper showing that methyl-coenzyme M reductase makes methane through a methyl radical intermediate[4](https://news.umich.edu/chemists-settle-longstanding-debate-on-how-methane-is-made-biologically/) |
| Honors | Fellow of the American Society for Microbiology and of the American Academy of Arts and Sciences[2](https://cse.umn.edu/chem/events/professor-steve-ragsdale) |
| Funding | Long-running NIH (GM39451) and DOE (DE-FG02-04ER15532) support for the CODH/ACS program[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC2100024/) |
## Education and career
Ragsdale was born in [Rome, Georgia](https://www.edgepedia.org/rome-georgia), in 1952. His doctoral-era training connected him to both founders of the acetate-synthesis field: he trained under Lars Ljungdahl as well as Wood, the scientists after whom the bacteria *Clostridium ljungdahlii* and *Acetobacterium woodii* were named.[6](https://doi.org/10.1002/biof.5520060102)
His academic career moved through three institutions. He was an Assistant Professor at the [University of Wisconsin–Milwaukee](https://www.edgepedia.org/university-of-wisconsin-milwaukee), then rose from Associate to Full Professor to a named chair of biochemistry at the University of Nebraska, and moved to the University of Michigan in 2007.[2](https://cse.umn.edu/chem/events/professor-steve-ragsdale) The University of Minnesota event biography calls the Nebraska chair the George Beadle Professorship.[2](https://cse.umn.edu/chem/events/professor-steve-ragsdale)
## Wood–Ljungdahl pathway and CO dehydrogenase/acetyl-CoA synthase
[The Wood](https://www.edgepedia.org/the-wood)–Ljungdahl pathway is an anaerobic route by which microbes fix carbon dioxide into acetyl-CoA. Globally, CO2 is fixed at a rate of 200 gigatons per year through six known pathways, and under anaerobic conditions the Wood–Ljungdahl pathway is a predominant CO2 sink.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC4002135/) According to *The Eastern and Western branches of the Wood/Ljungdahl pathway: how the East and West were won*, by 1971 B12 and methyltetrahydrofolate had been identified as key pieces of the acetate-synthesis puzzle, with Ljungdahl working on the methyl (Eastern) branch and Wood on the carboxyl (Western) branch.[6](https://doi.org/10.1002/biof.5520060102) In the methyl branch, a methyltransferase transfers the N5 methyl group of methyl-tetrahydrofolate to the cobalt center of a corrinoid iron-sulfur protein; the final steps of the pathway occur on carbon monoxide dehydrogenase/acetyl-CoA synthase.[6](https://doi.org/10.1002/biof.5520060102)
Ragsdale's central contribution to this pathway was to establish CODH as the condensing enzyme of acetyl-CoA synthesis. Ten years before he surveyed the enzyme in Chemical Reviews, he and Harland Wood proposed that the acetogenic CODH catalyzes the final steps of acetyl-CoA synthesis and should be renamed acetyl-CoA synthase. That proposal was controversial at the time because it required the existence of carbonyl, methyl, and acetyl enzyme adducts on the enzyme.[8](https://doi.org/10.1021/cr950058+) The enzyme complex is a nickel-iron-sulfur protein that enables microbial growth on CO2 and CO, and it contains a 140-angstrom channel through which CO migrates during catalysis, a feature that makes the system an unusually demanding problem in enzymology.[1](https://ies.engin.umich.edu/profile/ragsdale-stephen/) According to a 2023 *Journal of the American Chemical Society* paper, methyl- and acetyl-Ni intermediates of acetyl-CoA synthase formed during anaerobic CO2 and CO fixation were characterized, providing direct observations of the organometallic intermediates the early proposal had required.[9](https://doi.org/10.1021/jacs.3c01772)
## Methyl-coenzyme M reductase and biological methane
Methanogenic archaea produce 1 billion tons of methane per year and account for nearly all methane found on earth. [Methyl-coenzyme M reductase](https://www.edgepedia.org/methyl-coenzyme-m-reductase) (MCR) is the key enzyme in methanogenesis; its active site holds a nickel tetrapyrrole cofactor, F430, at the bottom of a 50-angstrom channel.[10](https://icbic2025.p.asnevents.com.au/days/2025-08-01/abstract/122793)
In 2016, according to Michigan News, Ragsdale was lead author of a Science study that settled a longstanding debate over how the enzyme makes methane, a question he had pursued for 25 years. The team slowed the reaction a thousandfold by hobbling the second half of the pathway and used electron paramagnetic resonance spectroscopy. The absence of a methyl-nickel EPR signal pointed away from a methyl-nickel intermediate, and computational modeling found that a methyl radical required the least energy to produce, less than half that of the alternative intermediate. The low-valent Ni(I) ion initiates cleavage of methyl-coenzyme M's C–S bond, generating a methyl radical that abstracts a hydrogen atom from coenzyme B to form methane.[4](https://news.umich.edu/chemists-settle-longstanding-debate-on-how-methane-is-made-biologically/) The reaction is also reversible: the enzyme can run in reverse to break down methane, which matters because methane is both a greenhouse gas and one of the major energy sources used worldwide.[4](https://news.umich.edu/chemists-settle-longstanding-debate-on-how-methane-is-made-biologically/) • [11](https://www.pnnl.gov/publications/nickel-sulfonate-mode-substrate-binding-forward-and-reverse-reactions-methyl-scom)
## Representative work
The 2016 Science paper is the work that best represents his program. It showed, through slowed reactions, EPR spectroscopy, and computational modeling, that MCR synthesizes methane through a highly reactive methyl radical rather than a methyl-nickel intermediate, resolving a mechanistic debate that had divided the methanogenesis field.[4](https://news.umich.edu/chemists-settle-longstanding-debate-on-how-methane-is-made-biologically/)
His reviews have framed the wider field: the 2007 review "Nickel and the Carbon Cycle" covers three nickel enzymes central to the carbon cycle, CO dehydrogenase, acetyl-CoA synthase, and methyl-coenzyme M reductase,[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC2100024/) and the 2014 Chemical Reviews article surveys the structure, function, and mechanism of CODH and acetyl-CoA synthase.[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC4002135/)
## Honors, funding and professional roles
Ragsdale is a Fellow of the American Society for Microbiology and a Fellow of the American Academy of Arts and Sciences.[2](https://cse.umn.edu/chem/events/professor-steve-ragsdale) His research is funded by NIH and DOE; the CODH/ACS program has been supported by NIH grant GM39451 and DOE grant DE-FG02-04ER15532.[1](https://ies.engin.umich.edu/profile/ragsdale-stephen/) • [5](https://pmc.ncbi.nlm.nih.gov/articles/PMC2100024/) His laboratory's techniques include transient and steady-state kinetics, spectroscopy, cell biology, genetics, and molecular biology.[1](https://ies.engin.umich.edu/profile/ragsdale-stephen/)
## Recent developments
Two recent results mark the current state of both enzyme systems. On the CODH/ACS side, the 2023 [Journal of the American Chemical Society](https://www.edgepedia.org/journal-of-the-american-chemical-society) paper directly characterized the methyl- and acetyl-Ni intermediates formed during anaerobic CO2 and CO fixation, closing a loop that began with the proposal that these adducts must exist.[9](https://doi.org/10.1021/jacs.3c01772) On the methane side, his group developed anaerobic crystal-growth methods that allowed 1.5-angstrom structures of active Ni(I)-MCR by [X-ray diffraction](https://www.edgepedia.org/x-ray-diffraction) and X-ray free electron laser methods, reported at ICBIC 2025. The structures show that inactive Ni(II)-MCR sits in a "locked-in" state while active Ni(I)-MCR is highly dynamic, and a methyl radical is seen spectroscopically at the transition state for methane synthesis.[10](https://icbic2025.p.asnevents.com.au/days/2025-08-01/abstract/122793)
## References
1. Ragsdale, Stephen – Institute for Energy Solutions, University of Michigan. https://ies.engin.umich.edu/profile/ragsdale-stephen/
2. Professor Steve Ragsdale, Department of Chemistry, University of Minnesota. https://cse.umn.edu/chem/events/professor-steve-ragsdale
3. Stephen Ragsdale, professional profile. https://www.linkedin.com/in/stephen-ragsdale-93544721
4. Chemists settle longstanding debate on how methane is made biologically, Michigan News. https://news.umich.edu/chemists-settle-longstanding-debate-on-how-methane-is-made-biologically/
5. Nickel and the Carbon Cycle, Journal of Inorganic Biochemistry 2007. https://pmc.ncbi.nlm.nih.gov/articles/PMC2100024/
6. The Eastern and Western branches of the Wood/Ljungdahl pathway: how the East and West were won, BioFactors. https://doi.org/10.1002/biof.5520060102
7. Structure, Function, and Mechanism of the Nickel Metalloenzymes, CO Dehydrogenase, and Acetyl-CoA Synthase, Chemical Reviews 2014. https://pmc.ncbi.nlm.nih.gov/articles/PMC4002135/
8. Nickel-Containing Carbon Monoxide Dehydrogenase/Acetyl-CoA Synthase, Chemical Reviews. https://doi.org/10.1021/cr950058+
9. Characterization of Methyl- and Acetyl-Ni Intermediates in Acetyl CoA Synthase Formed during Anaerobic CO2 and CO Fixation, JACS 2023. https://doi.org/10.1021/jacs.3c01772
10. Invited Talk, ICBIC 2025 abstract, ASN Events. https://icbic2025.p.asnevents.com.au/days/2025-08-01/abstract/122793
11. Nickel-Sulfonate Mode of Substrate Binding for Forward and Reverse Reactions of Methyl-SCoM Reductase Suggest a Radical Mechanism Involving Long Range Electron Transfer, https://www.pnnl.gov/publications/nickel-sulfonate-mode-substrate-binding-forward-and-reverse-reactions-methyl-scom
---
*Topic: Encyclopedia › Life and health › Life and health scientists › Life scientists › Researchers in structural biology, biochemistry, and biophysics › Metabolism and metabolic biochemistry › Metabolic pathway and enzyme researchers*
*Initially written Sep 21, 2026 · Reviewed: Sep 25, 2026 · Edited: Sep 25, 2026; Oct 15, 2026; Oct 21, 2026 · Last review: Sep 25, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license