I'm interested in the chemistry and biology of metabolic pathways that regulate the global carbon cycle. We work with microbes that make methane, fix carbon monoxide and carbon dioxide, isolate the enzymes responsible for these processes, and use kinetic, structural, and spectroscopic methods to characterize their mechanisms. This work has led to the discovery of an organometallic reaction sequence for the conversion of CO and CO2 into acetyl-CoA, a major precursor of many cellular metabolites. I'm also interested in the regulation of metabolic pathways in humans by metal ions with a major focus on iron and heme. This includes key proteins involved in iron uptake, heme synthesis and heme degradation. This work has led to the discovery of a regulatory network that interlinks redox and heme, allowing crosstalk between metal homeostasis and cellular redox states. Outside the lab, I practice yoga and play jazz guitar and enjoy reading and spending time with family and friends.

The students and postdoctoral scientists in my laboratory work at the interfaces between chemistry, biology, and physics and are studying processes that are important in the global carbon cycle, basic energy sciences, and in biomedical problems. We focus on three major areas: microbial metabolism of one-carbon compounds (CO, CO2, methane); the roles of metal ions in biology (including the mechanisms of nickel, B12, heme, and iron-sulfur enzymes); the regulation of metabolism and protein function by heme, CO, and thiol-disulfide redox switches. Techniques that we use in addressing research questions in these areas include transient and steady-state kinetics, spectroscopy, cell biology, genetics and molecular biology. The research is funded by NIH and DOE.

Microbial Methane Biosynthesis: Methanogens are masters at carbon dioxide reduction and the key enzyme in their metabolism is methyl coenzyme M reductase (MCR), which contains a nickel tetrapyrrolic cofactor. MCR is responsible for over 90 percent of all biologically generated methane on Earth. Based on recent studies in which we trapped intermediates in the MCR reaction mechanism and characterized them by spectroscopic and crystallographic methods, our work has revealed a mechanism for methane synthesis involving methyl radical intermediate.

Microbial CO2 and CO Metabolism: Anaerobic CO and CO2 metabolism play key roles in the global carbon cycle. We are characterizing a nickel-iron-sulfur (NiFeS) bifunctional protein complex called CO dehydrogenase/acetyl-CoA synthase (CODH/ACS) that is the central enzyme in the Wood-Ljungdahl pathway of anaerobic CO2 fixation. CODH/ACS enables microbial growth on CO2 and the toxic gas CO. In this complex, CODH reduces CO2 to CO, which migrates from the NiFeS active site of CODH through a 70 Å tunnel to the NiFeS active site of ACS, which catalyzes acetyl-CoA synthesis from CO, a methyl group (donated by a B12 containing enzyme), and CoA. We also are studying radical chemistry and methyl and proton transfer in a methyltransferase, a vitamin B12/iron-sulfur protein, and pyruvate ferredoxin oxidoreductase, which play key roles in this important component of the carbon cycle.

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 and CO. For example, 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 processes. We also have recently uncovered thiol/disulfide redox switches that regulate heme and CO binding to a potassium channel (BK channel) that interacts with HO2 and is involved in regulating oxygen levels in the blood stream and a key transcriptional regulator of the circadian cycle (Rev-Erb). Various in vivo and in vitro approaches are being used to study how redox and ligand (heme, CO, NO) binding regulate activity, protein-protein interactions and downstream metabolic events involving HO2, the BK channel, Rev-Erb and related systems.

Microbial Mercury Methylation: In collaboration with the Mercury Science Focus Area at Oak Ridge National Laboratory (ORNL) (link is external), we are studying the enzymes involved in methylation of mercury. Methylmercury (MeHg) is a neurotoxin and widespread environmental pollutant with no known biological function. Anaerobic microorganisms produce this highly toxic compound by methylating less toxic inorganic mercury (Hg) species in the environment, but the biosynthetic pathway by which this occurs is unknown. We are studying HgcA, a membrane-associated cobalamin-containing protein and HgcB, a soluble iron-sulfur protein.

The Ragsdale laboratory has been certified as a Platinum Level Sustainable Laboratory by the Office of Campus Sustainability at the University of Michigan.

The Ragsdale laboratory is committed to diversity, equity and inclusion. All are welcome, regardless of race, ethnicity, color, gender, sexual orientation, gender identity and expression, country of origin, religion, or disability status. We aim to maintain a safe space for academic, research, and personal growth; to respect the boundaries of others; and to treat others graciously and thoughtfully as we would like others to treat us.