Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism

Tibbetts, Anne S.; Appling, Dean R.

doi:10.1146/annurev.nutr.012809.104810

Cited by 695Folate and B Vitamins ResearchMetabolism and Genetic DisordersBiochemical and Molecular Research

Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism

Tibbetts, Anne S., Appling, Dean R.·2010·Annual Review of Nutrition

DOI 10.1146/annurev.nutr.012809.104810

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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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Self-citation
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The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
One-Carbon Metabolism in Health and Disease
Ducker, G. S., & Rabinowitz, J. D. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.009 · Cited by 2,239 · see citing works
“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).”
Method
The multifaceted contributions of mitochondria to cellular metabolism
Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935 · see citing works
Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation
Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A. L., Kafri, R., Kirschner, M. W., Clish, C. B., & Mootha, V. K. (2012) · Science · doi:10.1126/science.1218595 · Cited by 1,403 · see citing works
Quantitative flux analysis reveals folate-dependent NADPH production
Fan, J., Ye, J., Kamphorst, J. J., Shlomi, T., Thompson, C. B., & Rabinowitz, J. D. (2014) · Nature · doi:10.1038/nature13236 · Cited by 1,114 · see citing works
Biomarkers of Nutrition for Development—Folate Review
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 1,147 · see citing works
Serine and one-carbon metabolism in cancer
Yang, M., & Vousden, K. H. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.81 · Cited by 992 · see citing works
Mitochondrial disorders as windows into an ancient organelle
Vafai, S. B., & Mootha, V. K. (2012) · Nature · doi:10.1038/nature11707 · Cited by 733 · see citing works
Diabetic vascular diseases: molecular mechanisms and therapeutic strategies
Li, Y., Liu, Y., Liu, S., Gao, M., Wang, W., Chen, K., Huang, L., & Liu, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01400-z · Cited by 763 · see citing works
Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis
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 · see citing works
“CH2-THF contains the methylene group that fuels de novo thymidine synthesis from deoxyuridine in concert with pyrimidine biosynthesis and hence nucleotide synthesis during cell proliferation (Tibbetts and Appling, 2010).”
Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome
Hebert, A. S., Dittenhafer-Reed, K. E., Yu, W., Bailey, D. J., Selen, E. S., Boersma, M. D., Carson, J. J., Tonelli, M., Balloon, A. J., Higbee, A. J., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.10.024 · Cited by 636 · see citing works
“One-Carbon Metabolism One-carbon (1C) transfer reactions are essential for amino acid catabolism; transfer of methyl groups to DNA, RNA, and proteins; and in formylation of the initiator transfer RNA (tRNA) required for mitochondrial protein synthesis (Tibbetts and Appling, 2010).”
Neural Tube Defects
Greene, N. D. E., & Copp, A. J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062012-170354 · Cited by 656 · see citing works
“ACKNOWLEDGMENTS Work in the authors laboratory is funded by the Medical Research Council (J003794), Newlife Foundation (11-1206) and the Wellcome Trust (087525).”
BackgroundMethod
Endothelial Cell Metabolism in Normal and Diseased Vasculature
Eelen, G., de Zeeuw, P., Simons, M., & Carmeliet, P. (2015) · Circulation Research · doi:10.1161/circresaha.116.302855 · Cited by 619 · see citing works
A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate
Pacold, M. E., Brimacombe, K. R., Chan, S. H., Rohde, J. M., Lewis, C. A., Swier, L. J. Y. M., Possemato, R., Chen, W. W., Sullivan, L. B., Fiske, B. P., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2070 · Cited by 553 · see citing works
“Most of the remaining compounds contained a piperazine-1-carbothioamide scaffold, among which the compound we named PHGDH-hit (1) (Fig.”
Influential
Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells
Labuschagne, C. F., van den Broek, N. J. F., Mackay, G. M., Vousden, K. H., & Maddocks, O. D. K. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.045 · Cited by 576 · see citing works
“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.”
BackgroundInfluential
Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer
Nilsson, 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 · see citing works
Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells
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 · see citing works
“Resolving Compartmentalized NADPH Metabolism We observed transfer of 2H from [3-2H]glucose onto serine, suggesting that cytosolic MTHFD1 can operate in the reductive direction in these cells (Figure 5E).”
BackgroundInfluential
One-carbon metabolism in cancer
Newman, A. C., & Maddocks, O. D. K. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.118 · Cited by 511 · see citing works
“During this reaction, the onecarbon unit that is cleaved from serine is transferred to THF, generating methylene-THF (Tibbetts and Appling, 2010).”
Background
Vitamin 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 · see citing works
Mitochondrial dysfunction remodels one-carbon metabolism in human cells
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 439 · see citing works
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 · see citing works
Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway
Ducker, G. S., Chen, L., Morscher, R. J., Ghergurovich, J. M., Esposito, M., Teng, X., Kang, Y., & Rabinowitz, J. D. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.016 · Cited by 419 · see citing works
“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).”
Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells
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 440 · see citing works
“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).”
Background
Antifolates in cancer therapy: Structure, activity and mechanisms of drug resistance
Gonen, N., & Assaraf, Y. G. (2012) · Drug Resistance Updates · doi:10.1016/j.drup.2012.07.002 · Cited by 435 · see citing works
“In eukaryotes, folate metabolism is compartmentalized in two main subcellular compartments: the cytosol and mitochondria (Tibbetts and Appling, 2010).”
Background
Metabolism of Amino Acids in Cancer
Wei, Z. C., Liu, X., Cheng, C., Yu, W., & Yi, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.603837 · Cited by 439 · see citing works
“Glycine can also be cleaved by the mitochondrial glycine cleavage system to yield 5,10methylene-THF, which enters the folate cycle (Tibbetts and Appling, 2010).”
Background
NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism
Chen, L., Zhang, Z., Hoshino, A., Zheng, H. D., Morley, M. P., Arany, Z. P., & Rabinowitz, J. D. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0043-x · Cited by 419 · see citing works
The importance of serine metabolism in cancer
Mattaini, K. R., Sullivan, M. R., & Heiden, M. G. V. (2016) · The Journal of Cell Biology · doi:10.1083/jcb.201604085 · Cited by 409 · see citing works
Mitochondria as biosynthetic factories for cancer proliferation
Ahn, C. S., & Metallo, C. M. (2015) · Cancer & Metabolism · doi:10.1186/s40170-015-0128-2 · Cited by 399 · see citing works
“Additional evidence by others supports the concept that mitochondrial FOCM is an important contributor of reducing equivalents and one carbon intermediates for nucleotide biosynthesis [75,76].”
BackgroundInfluential
Inflammation, vitamin B6 and related pathways
Ueland, P. M., McCann, A., Midttun, Ø., & Ulvik, A. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.08.001 · Cited by 385 · see citing works
SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance
Kim, D., Fiske, B. P., Birsoy, K., Freinkman, E., Kami, K., Possemato, R. L., Chudnovsky, Y., Pacold, M. E., Chen, W. W., Cantor, J. R., et al. (2015) · Nature · doi:10.1038/nature14363 · Cited by 368 · see citing works
Hypoxia‐inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype
Semenza, G. L. (2016) · The EMBO Journal · doi:10.15252/embj.201695204 · Cited by 369 · see citing works
Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism
Burgos-Barragan, G., Wit, N., Meiser, J., Dingler, F. A., Pietzke, M., Mulderrig, L., Pontel, L. B., Rosado, I. V., Brewer, T. F., Cordell, R. L., et al. (2017) · Nature · doi:10.1038/nature23481 · Cited by 359 · see citing works
Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers
Mullarky, E., Lucki, N. C., Beheshti Zavareh, R., Anglin, J. L., Gomes, A. P., Nicolay, B. N., Wong, J. C. Y., Christen, S., Takahashi, H., Singh, P. K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521548113 · Cited by 333 · see citing works
“Alternatively, serine hydroxymethyltransferases (SHMTs) convert serine to glycine, concomitantly charging the folate pool with “one-carbon” units (4, 5).”
Background
One-Carbon Metabolism Supports S-Adenosylmethionine and Histone Methylation to Drive Inflammatory Macrophages
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 351 · see citing works
Endothelial Cell Metabolism in Health and Disease
Rohlenová, K., Veys, K., Santos, I. M., Bock, K. D., & Carmeliet, P. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.10.010 · Cited by 336 · see citing works
Targeting mitochondrial metabolism for precision medicine in cancer
Sainero‐Alcolado, L., Liaño-Pons, J., Ruiz-Pérez, M. V., & Arsenian‐Henriksson, M. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01022-y · Cited by 330 · see citing works
“While the methionine cycle occurs in the cytosol, folate-dependent one carbon metabolism synthesizes serine/consumes glycine in the cytosol and catabolizes serine/ produces glycine in mitochondria [56].”
Background
Therapeutic targets in cancer cell metabolism and autophagy
Cheong, H., Lü, C., Lindsten, T., & Thompson, C. B. (2012) · Nature Biotechnology · doi:10.1038/nbt.2285 · Cited by 316 · see citing works
Metabolomics and mass spectrometry imaging reveal channeled de novo purine synthesis in cells
Pareek, V., Tian, H., Winograd, N., & Benkovic, S. J. (2020) · Science · doi:10.1126/science.aaz6465 · Cited by 312 · see citing works
Developmental plasticity and developmental origins of non-communicable disease: Theoretical considerations and epigenetic mechanisms
Hanson, M. A., Godfrey, K. M., Lillycrop, K. A., Burdge, G. C., & Gluckman, P. D. (2011) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2010.12.008 · Cited by 298 · see citing works
Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling
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 · see citing works
“That not all mitochondrial functions were reduced was evident from increased expression levels for a group of genes with roles in folate-based one-carbon metabolism (MTHFD2, MTHFD1L, GLDC, SHMT2, SLC25A32) important for DNA synthesis, repair, and methylation (30).”
Background
Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism
Nikkanen, J., Forsström, S., Euro, L., Paetau, I., Kohnz, R. A., Wang, L., Chilov, D., Viinamäki, J., Roivainen, A., Marjamäki, P., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.01.019 · Cited by 285 · see citing works
“The cycle produces formyl-methionine for mitochondrial translation, nicotinamide adenine dinucleotide phosphate (NADPH) for membrane synthesis, and formate, which is the major 1C donor for cytoplasmic purine synthesis (Figure 1A; Tibbetts and Appling, 2010 ).”
Mitochondrial translation requires folate-dependent tRNA methylation
Morscher, R. J., Ducker, G. S., Li, H., Mayer, J., Gitai, Z., Sperl, W., & Rabinowitz, J. D. (2018) · Nature · doi:10.1038/nature25460 · Cited by 278 · see citing works
Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells
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 261 · see citing works
“The contribution of folate metabolism to purine synthesis has been studied extensively.(43,45) The contribution to ATP production supports our previous theoretical prediction implicating the SOG pathway in energy generation.”
Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma
Ducker, G. S., Ghergurovich, J. M., Mainolfi, N., Suri, V., Jeong, S. K., Hsin-Jung Li, S., Friedman, A., Manfredi, M. G., Gitai, Z., Kim, H., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1706617114 · Cited by 261 · see citing works
The ins and outs of serine and glycine metabolism in cancer
Geeraerts, S. L., Heylen, E., Keersmaecker, K. D., & Kampen, K. R. (2021) · Nature Metabolism · doi:10.1038/s42255-020-00329-9 · Cited by 250 · see citing works
Serine Availability Influences Mitochondrial Dynamics and Function through Lipid Metabolism
Gao, X., Lee, K., Reid, M. A., Sanderson, S. M., Qiu, C., Li, S., Liu, J., & Locasale, J. W. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.03.017 · Cited by 249 · see citing works
“…uthor M anuscript A uthor M anuscript Serine-derived folate metabolism is partitioned in mitochondrial and nucleocytoplasmic compartments, where it contributes to nucleotide and redox metabolism in both compartments (Ducker and Rabinowitz, 2017; Tibbetts and Appling, 2010; Yang and Vousden, 2016).”
Influential
SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism
Kory, N., Wyant, G. A., Prakash, G., de Bos, J. U., Bottanelli, F., Pacold, M. E., Chan, S. H., Lewis, C. A., Wang, T., Keys, H. R., et al. (2018) · Science · doi:10.1126/science.aat9528 · Cited by 246 · see citing works
Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function
Kurniawan, H., Franchina, D. G., Guerra, L., Bonetti, L., Soriano‐Baguet, L., Grusdat, M., Schlicker, L., Hunewald, O. E., Dostert, C., Merz, M. P., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.03.004 · Cited by 245 · see citing works
“Serine drives 1CMet because it provides its hydroxymethyl group as a one-carbon unit to tetrahydrofolate (Ducker and Rabinowitz, 2017; Herbig et al., 2002; Tibbetts and Appling, 2010).”
The Histone H3 Methyltransferase G9A Epigenetically Activates the Serine-Glycine Synthesis Pathway to Sustain Cancer Cell Survival and Proliferation
Ding, J., Li, T., Wang, X., Zhao, E., Choi, J.-H., Yang, L., Zha, Y., Dong, Z., Huang, S., Asara, J. M., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.004 · Cited by 244 · see citing works
“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.”
BackgroundResultInfluential
Formaldehyde in brain: an overlooked player in neurodegeneration?
Tulpule, K., & Dringen, R. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12356 · Cited by 238 · see citing works
Nutritional influences on epigenetics and age-related disease
Park, L. K., Friso, S., & Choi, S. (2011) · Proceedings of The Nutrition Society · doi:10.1017/s0029665111003302 · Cited by 242 · see citing works
“Choline also provides methyl groups for the folate-independent homocysteine remethylation reaction; together these demonstrate how nutrients can serve as the source of epigenetic modifications((11)).”
Protein Lysine Acylation and Cysteine Succination by Intermediates of Energy Metabolism
Lin, H., Su, X., & He, B. (2012) · ACS Chemical Biology · doi:10.1021/cb3001793 · Cited by 236 · see citing works
Toward a better understanding of folate metabolism in health and disease
Zheng, Y., & Cantley, L. C. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20181965 · Cited by 235 · see citing works
“Many excellent reviews on folate metabolism have appeared over the past decade, some of which cover metabolic compartmentation (Tibbetts and Appling, 2010; Scotti et al., 2013), folate transport (Zhao et al.”
Background
Formate metabolism in health and disease
Pietzke, M., Meiser, J., & Vazquez, A. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2019.05.012 · Cited by 218 · see citing works
“In proliferating cells, formate contributes to the 1C demand of purine and thymidylate synthesis [4,15] (Figure 2).”
BackgroundInfluential
The Intestinal Absorption of Folates
Visentin, M., Diop-Bove, N., Zhao, R., & Goldman, I. D. (2011) · Annual Review of Physiology · doi:10.1146/annurev-physiol-020911-153251 · Cited by 223 · see citing works
Undercover: gene control by metabolites and metabolic enzymesPreprint
van der Knaap, J. A., & Verrijzer, C. P. (2016) · Genes & Development · doi:10.1101/gad.289140.116 · Cited by 213 · see citing works
Principles of targeting endothelial cell metabolism to treat angiogenesis and endothelial cell dysfunction in disease
Goveia, J., Stapor, P. C., & Carmeliet, P. (2014) · EMBO Molecular Medicine · doi:10.15252/emmm.201404156 · Cited by 199 · see citing works
“One-carbon (1C) metabolism centers around the ability of folate-derived co-enzymes to carry activated 1C units (Fig 3) (Tibbetts & Appling, 2010).”
Chemiluminescent Probes for Activity‐Based Sensing of Formaldehyde Released from Folate Degradation in Living Mice
Bruemmer, K. J., Green, O., Su, T. A., Shabat, D., & Chang, C. J. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201802143 · Cited by 200 · see citing works
Formaldehyde metabolism and its impact on human health
Reingruber, H., & Pontel, L. B. (2018) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2018.07.001 · Cited by 192 · see citing works
Novel insights on interactions between folate and lipid metabolism
da Silva, R. P., Kelly, K. B., Rajabi, A. A., & Jacobs, R. L. (2013) · BioFactors · doi:10.1002/biof.1154 · Cited by 190 · see citing works
“The role of folate in one-carbon metabolism has been studied extensively; for comprehensive reviews of folate-mediated one-carbon metabolism see Tibbetts and Appling [2] and Stover and Field [3].”
Background
The Metabolic Mechanisms of Breast Cancer Metastasis
Wang, L., Zhang, S., & Wang, X. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.602416 · Cited by 191 · see citing works
The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation
Shang, M., Yang, H., Yang, R., Chen, T., Fu, Y., Li, Y., Fang, X.-L., Zhang, K., Jianju, Z., Li, H., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22173-5 · Cited by 184 · see citing works
Serine one-carbon catabolism with formate overflow
Meiser, J., Tumanov, S., Maddocks, O., Labuschagne, C. F., Athineos, D., Van Den Broek, N., Mackay, G. M., Gottlieb, E., Blyth, K., Vousden, K., et al. (2016) · Science Advances · doi:10.1126/sciadv.1601273 · Cited by 174 · see citing works
“The formate generated by MTHFD1L can also be recaptured by cytosolic 10CHO-THF synthetase (MTHFD1) to satisfy the one-carbon demand for de novo purine synthesis (1).”
BackgroundInfluential
Folic acid and primary prevention of neural tube defects: A review
van Gool, J. D., Hirche, H., Lax, H., & Schaepdrijver, L. D. (2018) · Reproductive Toxicology · doi:10.1016/j.reprotox.2018.05.004 · Cited by 174 · see citing works
Transforming Growth Factor (TGF)-β Promotes de Novo Serine Synthesis for Collagen Production
Nigdelioglu, R., Hamanaka, R. B., Meliton, A. Y., O'Leary, E., Witt, L. J., Cho, T., Sun, K., Bonham, C., Wu, D., Woods, P. S., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.756247 · Cited by 169 · see citing works
Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans
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 · see citing works
Serine and Functional Metabolites in Cancer
Newman, A. C., & Maddocks, O. D. K. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.05.001 · Cited by 166 · see citing works
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 165 · see citing works
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 163 · see citing works
“…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).”
Background
Molybdenum 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 159 · see citing works
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 · see citing works
“Wiley Interdiscip Rev Syst Biol Med 2(4):471–480.”
BackgroundInfluentialSelf-citation
Metabolic consequences of oncogenic IDH mutations
Parker, S. J., & Metallo, C. M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.05.003 · Cited by 158 · see citing works
“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).”
Background
The 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 · see citing works
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 152 · see citing works
“MTHFD1L therefore plays critical roles in folate cycle maintenance (10).”
Background
Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications
Vergote, I. B., Marth, C., & Coleman, R. L. (2015) · Cancer and Metastasis Reviews · doi:10.1007/s10555-014-9539-8 · Cited by 148 · see citing works
Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice
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 · see citing works
“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 .”
Development of a General Aza-Cope Reaction Trigger Applied to Fluorescence Imaging of Formaldehyde in Living Cells
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 140 · see citing works
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 139 · see citing works
“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].”
Background
Metabolic 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 135 · see citing works
Trafficking of Intracellular Folates
Stover, P. J., & Field, M. S. (2011) · Advances in Nutrition · doi:10.3945/an.111.000596 · Cited by 135 · see citing works
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 135 · see citing works
“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 128 · see citing works
“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 · see citing works
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 125 · see citing works
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 130 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
Serine Hydroxymethyltransferase Anchors de Novo Thymidylate Synthesis Pathway to Nuclear Lamina for DNA Synthesis
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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
DOI: 10.1146/annurev.nutr.012809.104810
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 › Medicine › Rheumatology › 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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Compartmentalization of Mammalian Folate-Mediated One-Carbon Metabolism

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