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One-Carbon Metabolism in Health and Disease
Open accessAbstract
One-carbon (1C) metabolism, mediated by the folate cofactor, supports multiple physiological processes. These include biosynthesis (purines and thymidine), amino acid homeostasis (glycine, serine, and methionine), epigenetic maintenance, and redox defense. Both within eukaryotic cells and across organs, 1C metabolic reactions are compartmentalized. Here we review the fundamentals of mammalian 1C metabolism, including the pathways active in different compartments, cell types, and biological states. Emphasis is given to recent discoveries enabled by modern genetics, analytical chemistry, and isotope tracing. An emerging theme is the biological importance of mitochondrial 1C reactions, both for producing 1C units that are exported to the cytosol and for making additional products, including glycine and NADPH. Increased clarity regarding differential folate pathway usage in cancer, stem cells, development, and adult physiology is reviewed and highlights new opportunities for selective therapeutic intervention.
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“formate triggered an upregulation of differentially expressed genes (DEGs) involved in 1C metabolism, such as serine hydroxymethyltransferase 2 (Shmt2)42,58 and cystathionine gamma-lyase (Cth)59, as well as genes regulated by Nrf2 (e.g.: Cth60, NADH dehydrogenase 4 (mt-Nd4)61 and transketolase (Tkt)62,63) (Figure 6L and Table S3).”
From Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy (2025) · cites this paper as [42]
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“The co-factor tetrahydrofolate (THF) is the carrier that mediates 1C transfer reactions for de novo nucleotide synthesis.66,67”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [66]
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“Mitochondrial contributions to this pathway are critical, as mitochondrial formate is the main carbon source for cytosolic 1C metabolism 66”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [66]
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“Increasing the intensity of anabolism requires the coordinated up-regulation of a number of biosynthetic processes, for which glycolysis and one-carbon metabolism are crucial sources of structural units [37,45,46].”
From 20-Hydroxyecdysone Boosts Energy Production and Biosynthetic Processes in Non-Transformed Mouse Cells (2024) · cites this paper as [46]
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Metadata
- Authors
- Ducker, G. S., & Rabinowitz, J. D.
- Affiliations
- Princeton University (US)
- Corresponding author
- Rabinowitz, Joshua D.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 25
- Issue
- 1
- Pages
- 27-42
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5353360
- OpenAlex
- W2520894026
- Cited by
- 2,239
- References
- 153
- Citations by year
- 2026: 366 · 2025: 308 · 2024: 316 · 2023: 250 · 2022: 263 · 2021: 261 · 2020: 205 · 2019: 144 · 2018: 80 · 2017: 41
- FWCI
- 14.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Stand Up To Cancer
- National Cancer Institute (R01CA163591)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK019525)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- one-carbon metabolism, folic acid, folate pathway, purine biosynthesis, thymidine biosynthesis, amino acid homeostasis, methionine metabolism, serine metabolism, glycine metabolism, epigenetic maintenance, redox defense, NADPH production, isotope tracing, cancer metabolism, stem cells, development (biology)
- MeSH terms
- Animals, Carbon, Disease, Health, Humans, Mitochondria, Neoplasms, Metabolic Networks and Pathways
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