Serine one-carbon catabolism with formate overflow
Open accessAbstract
Serine catabolism to glycine and a one-carbon unit has been linked to the anabolic requirements of proliferating mammalian cells. However, genome-scale modeling predicts a catabolic role with one-carbon release as formate. We experimentally prove that in cultured cancer cells and nontransformed fibroblasts, most of the serine-derived one-carbon units are released from cells as formate, and that formate release is dependent on mitochondrial reverse 10-CHO-THF synthetase activity. We also show that in cancer cells, formate release is coupled to mitochondrial complex I activity, whereas in nontransformed fibroblasts, it is partially insensitive to inhibition of complex I activity. We demonstrate that in mice, about 50% of plasma formate is derived from serine and that serine starvation or complex I inhibition reduces formate synthesis in vivo. These observations transform our understanding of one-carbon metabolism and have implications for the treatment of diabetes and cancer with complex I inhibitors.
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Serine production is of particular significance because serine is a major substrate for the folate/one-carbon cycle whose metabolites contribute to various cellular biosynthetic and regulatory processes.
“Of particular significance is serine production because it is a major substrate for the folate/one-carbon cycle whose metabolites contribute to various cellular biosynthetic and regulatory processes (212, 213).”
From Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease (2018) · cites this paper as [213]
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Metformin Is a Pyridoxal-5′-phosphate (PLP)-Competitive Inhibitor of SHMT2
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Mitochondrial Dysfunction and Metabolic Disturbances Induced by Viral Infections
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The emerging role of one-carbon metabolism in T cells
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MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions
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Metformin: Sentinel of the Epigenetic Landscapes That Underlie Cell Fate and Identity
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Metformin: Targeting the Metabolo-Epigenetic Link in Cancer Biology
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Metabolic Potential of Cancer Cells in Context of the Metastatic Cascade
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Actionable Metabolic Pathways in Heart Failure and Cancer—Lessons From Cancer Cell Metabolism
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Endo- and Exometabolome Crosstalk in Mesenchymal Stem Cells Undergoing Osteogenic Differentiation
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Formate promotes invasion and metastasis in reliance on lipid metabolism
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Cystathionine-γ-lyase drives antioxidant defense in cysteine-restricted IDH1-mutant astrocytomas
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Exploring the Role of Metabolites in Cancer and the Associated Nerve Crosstalk
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Serine metabolism is crucial for cGAS-STING signaling and viral defense control in the gut
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One-carbon metabolism in cancer cells: a critical review based on a core model of central metabolism
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Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer
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PKM2 diverts glycolytic flux in dependence on mitochondrial one-carbon cycle
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Presenting metabolomics analyses: what’s in a number?
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Association between gut health and gut microbiota in a polluted environment
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The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism
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Serine synthesis and catabolism in starved lung cancer and primary bronchial epithelial cells
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- Authors
- Meiser, J., Tumanov, S., Maddocks, O., Labuschagne, C. F., Athineos, D., Van Den Broek, N., Mackay, G. M., Gottlieb, E., Blyth, K., Vousden, K., Kamphorst, J. J., & Vazquez, A.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- University of Glasgow (GB)
- Cancer Research UK Beatson Institute, Glasgow, UK
- ORCID
- Venue
- Science Advances
- Published
- 2016-10-07
- Volume
- 2
- Issue
- 10
- Pages
- e1601273-e1601273
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC5091358
- OpenAlex
- W2539462439
- Cited by
- 174
- References
- 30
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 31 · 2023: 17 · 2022: 20 · 2021: 18 · 2020: 17 · 2019: 14 · 2018: 12 · 2017: 15
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Funders
- Cancer Research UK (ID0EQQBI11250, C596/A21140, ID0EXUBI11251, C596/A18076, ID0EIVBI11252, C596/A17196)
- DFG Fellowship Grant (ID0ET2BI11253, ME 4636/2-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- serine catabolism, one-carbon metabolism, mitochondrial complex I, cancer cells, fibroblasts, complex I inhibitors, glycine synthesis
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