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Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism
Abstract
The recognition that mitochondria participate in folate-mediated one-carbon metabolism grew out of pioneering work beginning in the 1950s from the laboratories of D.M. Greenberg, C.G. Mackenzie, and G. Kikuchi. These studies revealed mitochondria as the site of oxidation of one-carbon donors such as serine, glycine, sarcosine, and dimethylglycine. Subsequent work from these laboratories and others demonstrated the participation of folate coenzymes and folate-dependent enzymes in these mitochondrial processes. Biochemical and molecular genetic approaches in the 1980s and 1990s identified many of the enzymes involved and revealed an interdependence of cytoplasmic and mitochondrial one-carbon metabolism. These studies led to the development of a model of eukaryotic one-carbon metabolism that comprises parallel cytosolic and mitochondrial pathways, connected by one-carbon donors such as serine, glycine, and formate. Sequencing of the human and other mammalian genomes has facilitated identification of the enzymes that participate in this intercompartmental one-carbon metabolism, and animal models are beginning to clarify the roles of the cytoplasmic and mitochondrial isozymes of these enzymes. Identifying the mitochondrial transporters for the one-carbon donors and elucidating how flux through these pathways is controlled are two areas ripe for exploration.
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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 [67]
Citations
Cites
The Metabolic and Molecular Bases of Inherited Disease
Scriver, R. C. (1995) · Medical Entomology and Zoology · Cited by 12,101
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442
The metabolic and molecular bases of inherited disease
Chen, Y.-T. (2001) · Medical Entomology and Zoology · Cited by 6,928
Genomewide Association Analysis of Coronary Artery Disease
Samani, N. J., Erdmann, J., Hall, A. S., Hengstenberg, C., Mangino, M., Mayer, B., Dixon, R. J., Meitinger, T., Braund, P., Wichmann, H.-E., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa072366 · Cited by 2,044
Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside
Pebay‐Peyroula, E., Dahout-Gonzalez, C., Kahn, R., Trézéguet, V., Lauquin, G. J. ‐., & Brandolin, G. (2003) · Nature · doi:10.1038/nature02056 · Cited by 998
The mitochondrial transporter family (SLC25): physiological and pathological implications
Palmieri, F. (2004) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-003-1099-7 · Cited by 764
Wojtczak, L., & Kaniuga, Z. (1966) · Nature · doi:10.1038/2111239a0 · Cited by 691
Chapter 1 Folate‐Mediated One‐Carbon Metabolism
Fox, J. T., & Stover, P. J. (2008) · Vitamins & Hormones · doi:10.1016/s0083-6729(08)00401-9 · Cited by 402
Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia
Kikuchi, G., Motokawa, Y., Yoshida, T., & Hiraga, K. (2008) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.84.246 · Cited by 381
GENETICS OF SOMATIC MAMMALIAN CELLS
Puck, T. T., & Fisher, H. W. (1956) · The Journal of Experimental Medicine · doi:10.1084/jem.104.3.427 · Cited by 375
Research works printed but not linked: 7
- Barlowe CK, 1988, Biofactors, 1, 171
- Garrow TA, 2001, Homocysteine in Health and Disease, 145
- Kao FT, 1975, Genetics, 79, 343
- Sheid B, 1968, Cancer Res., 28, 2512
- Trippett TM, 2001, Cancer Res., 61, 1941
- Veech RL, 1987, Pyridine Nucleotide Coenzymes. Chemical, Biochemical, and Medical Aspects, Part B, 79
- Wang FK, 1967, Biochem. Z., 346, 458
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“Mitochondrial NAD+/NADH ratios are maintained by oxidative phosphorylation, and early experiments in isolated mitochondria showed that formate production from serine was respiration dependent (Garcı́a-Martı́nez and Appling, 1993).”
MethodThe multifaceted contributions of mitochondria to cellular metabolism
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Bailey, L. B., Stover, P. J., McNulty, H., Fenech, M. F., Gregory, J. F., Mills, J. L., Pfeiffer, C. M., Fazili, Z., Zhang, M., Ueland, P. M., et al. (2015) · Journal of Nutrition · doi:10.3945/jn.114.206599 · Cited by 1,170
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Zhang, W. C., Shyh-Chang, N., Yang, H., Rai, A., Umashankar, S., Ma, S., Soh, B. S., Sun, L. L., Tai, B. C., Nga, M. E., et al. (2012) · Cell · doi:10.1016/j.cell.2011.11.050 · Cited by 660
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“ACKNOWLEDGMENTS Work in the authors laboratory is funded by the Medical Research Council (J003794), Newlife Foundation (11-1206) and the Wellcome Trust (087525).”
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“Most of the remaining compounds contained a piperazine-1-carbothioamide scaffold, among which the compound we named PHGDH-hit (1) (Fig.”
InfluentialSerine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells
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“The present lack of clarity is due, at least in part, to the complexity of serine and glycine metabolism, which can be carried out by mitochondrial and cytoplasmic pathways (Tibbetts and Appling, 2010), both of which are upregulated in cancer (Jain et al.”
BackgroundInfluentialNilsson, R., Jain, M., Madhusudhan, N., Sheppard, N. G., Strittmatter, L., Kampf, C., Huang, J., Asplund, A., & Mootha, V. K. (2014) · Nature Communications · doi:10.1038/ncomms4128 · Cited by 607
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Lewis, C. A., Parker, S. J., Fiske, B. P., McCloskey, D., Gui, D. Y., Green, C. R., Vokes, N. I., Feist, A. M., Vander Heiden, M. G., & Metallo, C. M. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.008 · Cited by 562
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BackgroundInfluentialOne-carbon metabolism in cancer
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BackgroundVitamin B 12 , folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation
Froese, D. S., Fowler, B., & Baumgartner, M. R. (2019) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12009 · Cited by 479
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Bao, X. R., Ong, S., Goldberger, O., Peng, J., Sharma, R., Thompson, D. A., Vafai, S. B., Cox, A. G., Marutani, E., Ichinose, F., et al. (2016) · eLife · doi:10.7554/elife.10575 · Cited by 450
Serine Catabolism Regulates Mitochondrial Redox Control during Hypoxia
Ye, J., Fan, J., Venneti, S., Wan, Y.-W., Pawel, B. R., Zhang, J., Finley, L. W. S., Lu, C., Lindsten, T., Cross, J. R., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0250 · Cited by 452
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“We find, however, that, consistent with most prior literature on this topic, cytosolic 1C pathway fluxes in most proliferating cells are typically running in the direction from 10-formyl-THF to methylene-THF and therefore are consuming, not producing, NADPH (Tibbetts and Appling, 2010).”
Maddocks, O. D. K., Labuschagne, C. F., Adams, P. D., & Vousden, K. H. (2016) · Molecular Cell · doi:10.1016/j.molcel.2015.12.014 · Cited by 452
“DISCUSSION One of the most important cellular uses for serine is to provide one-carbon units to support the THF-cycle (Tibbetts and Appling, 2010).”
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Gonen, N., & Assaraf, Y. G. (2012) · Drug Resistance Updates · doi:10.1016/j.drup.2012.07.002 · Cited by 444
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Semenza, G. L. (2016) · The EMBO Journal · doi:10.15252/embj.201695204 · Cited by 380
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Yu, W., Wang, Z., Zhang, K., Chi, Z., Xu, T., Jiang, D., Chen, S., Li, W., Yang, X., Zhang, X., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.06.039 · Cited by 362
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den Boon, J. A., Pyeon, D., WANG, S. S., Horswill, M. A., SCHIFFMAN, M. H., Sherman, M. E., Zuna, R. E., Wang, Z., Hewitt, S. M., Pearson, R., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509322112 · Cited by 293
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Mitochondrial translation requires folate-dependent tRNA methylation
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Tedeschi, P. M., Markert, E. K., Gounder, M. K., Lin, H., Dvorzhinski, D., Dolfi, S. C., Chan, L. L.-Y., Qiu, J., DiPaola, R. S., Hirshfield, K. M., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.393 · Cited by 265
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“904 Cell Metabolism 18, 896–907, December 3, 2013 ª2013 Elsevier Importantly, we present evidence suggesting that the generation of 5,10-MTHF is crucial for the function of the serine-glycine biosynthetic pathway in promoting cancer cell survival and proliferation.”
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Yan, J., Jiang, X., West, A. A., Perry, C. A., Malysheva, O., Devapatla, S., Pressman, E. K., Vermeylen, F., Stabler, S. P., Allen, R. H., et al. (2012) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.111.022772 · Cited by 173
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Metabolic Pathways Fueling the Endothelial Cell Drive
Li, X., Kumar, A., & Carmeliet, P. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020518-114731 · Cited by 172
Human de novo purine biosynthesis
Pareek, V., Pedley, A. M., & Benkovic, S. J. (2020) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2020.1832438 · Cited by 161
“…and formate, mitochondria are the primary production site, and their utilization in the DNPB pathway requires their transport to the cytoplasm where DNPB is performed (Palmieri, 2013; Vettore, Westbrook, and Tennant, 2020; Tibbetts and Appling, 2010; Ducker and Rabinowitz, 2017; Kory et al., 2018).”
BackgroundMolybdenum and tungsten-dependent formate dehydrogenases
Maia, L. B., Moura, J. J. G., & Moura, I. (2014) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-014-1218-2 · Cited by 164
Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice
Momb, J., Lewandowski, J. P., Bryant, J. D., Fitch, R. D., Surman, D. R., Vokes, S. A., & Appling, D. R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211199110 · Cited by 160
“Wiley Interdiscip Rev Syst Biol Med 2(4):471–480.”
BackgroundInfluentialSelf-citationMetabolic consequences of oncogenic IDH mutations
Parker, S. J., & Metallo, C. M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.003 · Cited by 162
“These enzymes include malic enzymes (ME), isocitrate dehydrogenases (IDH), aldehyde dehydrogenases (ALDH), and methylene tetrahydrofolate dehydrogenases (MTHFD) (Pollak et al., 2007; Tibbetts & Appling, 2010; Lunt & Vander Heiden, 2011).”
BackgroundThe human proton-coupled folate transporter
Desmoulin, S. K., Hou, Z., Gangjee, A., & Matherly, L. H. (2012) · Cancer Biology & Therapy · doi:10.4161/cbt.22020 · Cited by 158
Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma
Lee, D., Xu, M., Chiu, D. K., Lai, R. K., Tse, A. P., Li, L. L., Law, C., Tsang, F. H., Wei, L. L., Chan, C. Y., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90253 · Cited by 153
“MTHFD1L therefore plays critical roles in folate cycle maintenance (10).”
BackgroundVergote, I. B., Marth, C., & Coleman, R. L. (2015) · Cancer and Metastasis Reviews · doi:10.1007/s10555-014-9539-8 · Cited by 148
Pai, Y. J., Leung, K., Savery, D., Hutchin, T. P., Prunty, H., Heales, S., Brosnan, M. E., Brosnan, J. T., Copp, A. J., & Greene, N. D. E. (2015) · Nature Communications · doi:10.1038/ncomms7388 · Cited by 144
“Mitochondrial FOCM generates formate, with the principal one-carbon donors being serine (catalysed by Shmt2) or glycine (mediated by the GCS) with additional contribution from dimethylglycine and sarcosine 2,32 .”
Bruemmer, K. J., Walvoord, R. R., Brewer, T. F., Burgos-Barragan, G., Wit, N., Pontel, L. B., Patel, K. J., & Chang, C. J. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.6b12460 · Cited by 142
Glycine: The Smallest Anti-Inflammatory Micronutrient
Aguayo-Cerón, K. A., Sánchez‐Muñoz, F., Gutiérrez-Rojas, R. A., Acevedo-Villavicencio, L. N., Flores-Zarate, A. V., Huang, F., Giacoman‐Martínez, A., Villafaña, S., & Romero‐Nava, R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411236 · Cited by 147
“Glycine, also known as amino acetic acid, is an important component of many proteins and plays a crucial role in the synthesis of many biomolecules, including creatine and purine nucleotides [1].”
BackgroundMetabolic requirements for cancer cell proliferation
Keibler, M. A., Wasylenko, T. M., Kelleher, J. K., Iliopoulos, O., Heiden, M. G. V., & Stephanopoulos, G. N. (2016) · Cancer & Metabolism · doi:10.1186/s40170-016-0156-6 · Cited by 141
Trafficking of Intracellular Folates
Stover, P. J., & Field, M. S. (2011) · Advances in Nutrition · doi:10.3945/an.111.000596 · Cited by 135
One carbon metabolism in pregnancy: Impact on maternal, fetal and neonatal health
Kalhan, S. C. (2016) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2016.06.006 · Cited by 137
“The reader is referred to outstanding scholarly reviews for details (Tibbetts and Appling, 2010; Christensen and MacKenzie, 2006; Stover and Field, 2011; Fox and Stover, 2008, Lu and Mato, 2012).”
Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage
Liu, L., Shah, S., Fan, J., Park, J. O., Wellen, K. E., & Rabinowitz, J. D. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2047 · Cited by 130
“Combining equations (1) and (2), the measured absolute oxPPP NADPH production (f NADPH from oxPPP, 0.”
SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia
García‐Cañaveras, J. C., Lancho, O., Ducker, G. S., Ghergurovich, J. M., Xu, X., da Silva-Diz, V., Minuzzo, S. A., Indraccolo, S., Kim, H., Herranz, D., et al. (2020) · Leukemia · doi:10.1038/s41375-020-0845-6 · Cited by 129
Nuclear metabolism and the regulation of the epigenome
Boon, R., da Silveira, G. G., & Mostoslavsky, R. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00285-4 · Cited by 129
Role of mitochondria in liver metabolic health and diseases
Morio, B., Panthu, B., Bassot, A., & Rieusset, J. (2020) · Cell Calcium · doi:10.1016/j.ceca.2020.102336 · Cited by 136
Reprogramming of serine, glycine and one-carbon metabolism in cancer
Li, A. M., & Ye, J. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165841 · Cited by 127
Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy
Yang, C., Zhang, J., Liao, M., Yang, Y., Wang, Y., Yuan, Y., & Ouyang, L. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.12.006 · Cited by 126
Lysosome-targeted carbon dots for ratiometric imaging of formaldehyde in living cells
Liu, H., Sun, Y., Li, Z., Yang, J., Aryee, A. A., Qu, L., Du, D., & Lin, Y. (2019) · Nanoscale · doi:10.1039/c9nr01678c · Cited by 125
Anderson, D. D., Woeller, C. F., Chiang, E. I., Shane, B., & Stover, P. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.333120 · Cited by 124
“Folate-mediated one-carbon metabolism is compartmentalized in the mitochondria, nucleus, and cytoplasm of eukaryotic cells (5).”
BackgroundThe complexity of the serine glycine one-carbon pathway in cancer
Reina‐Campos, M., Díaz-Meco, M. T., & Moscat, J. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201907022 · Cited by 125
“Many of the SGOCP’s enzymes also rely on the NADPH/NADP ratio, with the mitochondrial matrix having a much higher NADP/NADPH ratio than that of the cytosol (Tibbetts and Appling, 2010).”
BackgroundFolate metabolic pathways in Leishmania
Vickers, T. J., & Beverley, S. M. (2011) · Essays in Biochemistry · doi:10.1042/bse0510063 · Cited by 122
“In mammals and yeast, metabolic labelling suggests that the formation of mitochondrial methylene-H4F through the activities of FTL and DHCH is a major source of active C1 units [53].”
Fluorescent probes for imaging formaldehyde in biological systems
Bruemmer, K. J., Brewer, T. F., & Chang, C. J. (2017) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2017.04.010 · Cited by 122
“Introduction Formaldehyde (FA) is an endogenously-produced reactive carbonyl species (RCS) released in biological processes ranging from epigenetics to one carbon metabolism (Figure 1) [1,2].”
BackgroundIncreased plasma trimethylamine- N -oxide is associated with incident atrial fibrillation
Svingen, G. F. T., Zuo, H., Ueland, P. M., Seifert, R., Løland, K. H., Pedersen, E. R., Schuster, P. M., Karlsson, T. R., Tell, G. S., Schartum-Hansen, H., et al. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2018.04.128 · Cited by 123
Zhang, Y., Yang, Y., He, X., Yang, P., Zong, T., Sun, P., Sun, R., Yu, T., & Jiang, Z. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16602 · Cited by 122
Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition
Lee, J. Y., Friso, S., & Choi, S. (2014) · Nutrients · doi:10.3390/nu6083303 · Cited by 125
“After transferring the methyl group, SAM is converted to S-adenosylhomocysteine (SAH), which is an inhibitor of methyltransferases such as DNMTs and HMTs [124].”
MethodNarisawa, A., Komatsuzaki, S., Kikuchi, A., Niihori, T., Aoki, Y., Fujiwara, K., Tanemura, M., Hata, A., Suzuki, Y., Relton, C. L., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr585 · Cited by 119
“1A) (10).”
Increased formate overflow is a hallmark of oxidative cancer
Meiser, J., Schuster, A. M., Pietzke, M., Voorde, J. V., Athineos, D., Oizel, K., Burgos-Barragan, G., Wit, N., Dhayade, S., Morton, J. P., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03777-w · Cited by 119
Folate metabolism: a re-emerging therapeutic target in haematological cancers
Zarou, M. M., Vázquez, A., & Helgason, G. V. (2021) · Leukemia · doi:10.1038/s41375-021-01189-2 · Cited by 120
“Interestingly, studies have revealed that this subcellular compartmentalisation is conserved from yeast to mammalian cells [16].”
BackgroundMihajlovic, M., & Vinken, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063315 · Cited by 132
“Hepatic mitochondria also possess a complete set of enzymes needed for one-carbon (1C) metabolism, which includes both the methionine and folate cycles and that serves to generate methyl groups (one-carbon units) used for biosynthetic processes [26], in particular, the synthesis of purine and thymidine, polyamines ami…”
BackgroundMTHFD2 links RNA methylation to metabolic reprogramming in renal cell carcinoma
Green, N. H., Galvan, D. L., Badal, S. S., Chang, B. H., LeBleu, V. S., Long, J., Jonasch, E., & Danesh, F. R. (2019) · Oncogene · doi:10.1038/s41388-019-0869-4 · Cited by 119
Metadata
- Authors
- Tibbetts, A. S., & Appling, D. R.
- Affiliations
- The University of Texas at Austin (US)
- ORCID
- Appling, Dean R.
- Venue
- Annual Review of Nutrition
- Publisher
- Annual Reviews
- Published
- 2010-07-01
- Volume
- 30
- Issue
- 1
- Pages
- 57-81
- ISSN
- 0199-9885 (ISSN-L)
- 1545-4312
- OpenAlex
- W2145912883
- Cited by
- 692
- References
- 157
- Citations by year
- 2026: 42 · 2025: 40 · 2024: 40 · 2023: 53 · 2022: 70 · 2021: 55 · 2020: 61 · 2019: 61 · 2018: 55 · 2017: 33 · 2016: 51 · 2015: 26 · 2014: 33 · 2013: 28 · 2012: 27
- FWCI
- 3.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annual Review of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- mitochondrial metabolism, glycine oxidation, folate coenzymes, folate-dependent enzymes, serine, glycine, formate, isozymes, metabolic flux control
- MeSH terms
- Animals, Cell Nucleus, Cytoplasm, Folic Acid, Humans, Mammals, Mitochondria, One-Carbon Group Transferases
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