Mode of action uncovered for the specific reduction of methane emissions from ruminants by the small molecule 3-nitrooxypropanol
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Ruminants, such as cows, sheep, and goats, predominantly ferment in their rumen plant material to acetate, propionate, butyrate, CO2, and methane. Whereas the short fatty acids are absorbed and metabolized by the animals, the greenhouse gas methane escapes via eructation and breathing of the animals into the atmosphere. Along with the methane, up to 12% of the gross energy content of the feedstock is lost. Therefore, our recent report has raised interest in 3-nitrooxypropanol (3-NOP), which when added to the feed of ruminants in milligram amounts persistently reduces enteric methane emissions from livestock without apparent negative side effects [Hristov AN, et al. (2015) Proc Natl Acad Sci USA 112(34):10663-10668]. We now show with the aid of in silico, in vitro, and in vivo experiments that 3-NOP specifically targets methyl-coenzyme M reductase (MCR). The nickel enzyme, which is only active when its Ni ion is in the +1 oxidation state, catalyzes the methane-forming step in the rumen fermentation. Molecular docking suggested that 3-NOP preferably binds into the active site of MCR in a pose that places its reducible nitrate group in electron transfer distance to Ni(I). With purified MCR, we found that 3-NOP indeed inactivates MCR at micromolar concentrations by oxidation of its active site Ni(I). Concomitantly, the nitrate ester is reduced to nitrite, which also inactivates MCR at micromolar concentrations by oxidation of Ni(I). Using pure cultures, 3-NOP is demonstrated to inhibit growth of methanogenic archaea at concentrations that do not affect the growth of nonmethanogenic bacteria in the rumen.
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Inhibition of methyl-coenzyme M reductase can result in a reduction in rumen methanogenesis (up to 30%) without negative effects to the animal.
“This enzyme catalyzes the last step of methane-forming reactions (Duin et al., 2016) and its inhibition can result in a reduction in rumen methanogenesis (up to 30%) without negative effects to the animal (Hristov et al., 2015).”
From Addressing global ruminant agricultural challenges through understanding the rumen microbiome: past, present, and future (2018) · cites this paper as Duin et al., 2016
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- Authors
- Duin, E. C., Wagner, T., Shima, S., Prakash, D., Cronin, B., Yáñez-Ruiz, D. R., Duval, S., Rümbeli, R., Stemmler, R. T., Thauer, R. K., & Kindermann, M.
- Affiliations
- Auburn University (US)
- Max Planck Institute for Terrestrial Microbiology (DE)
- Estación Experimental del Zaidín, Consejo Superior de Investigaciones Cientificas, 18008 Granada, Spain;
- Research Centre for Animal Nutrition and Health, DSM Nutritional Products France, 68305 Saint Louis, France;
- Research and Development, DSM Nutritional Products, 4002 Basel, Switzerland
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2016-05-02
- Volume
- 113
- Issue
- 22
- Pages
- 6172-6177
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4896709
- OpenAlex
- W2345657234
- Cited by
- 339
- References
- 66
- Citations by year
- 2026: 44 · 2025: 59 · 2024: 56 · 2023: 40 · 2022: 40 · 2021: 30 · 2020: 18 · 2019: 25 · 2018: 14 · 2017: 8 · 2016: 5
- FWCI
- 35.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Max-Planck-Gesellschaft (no number)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Agronomy and Crop Science › Ruminant Nutrition and Digestive Physiology
- Physical Sciences › Engineering › Building and Construction › Anaerobic Digestion and Biogas Production
- Physical Sciences › Environmental Science › Ecology › Agriculture Sustainability and Environmental Impact
- Keywords
- 3-nitrooxypropanol, enteric methane, ruminants, methyl-coenzyme M reductase, rumen fermentation, methanogenesis inhibition, nickel enzymes, nitrate reduction, nitrite, methanogenic archaea, feed additives, greenhouse gas emissions reduction
- MeSH terms
- Animals, Methane, Oxidoreductases, Rumen, Ruminants, Euryarchaeota, Molecular Docking Simulation
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