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The Key Role of Anaplerosis and Cataplerosis for Citric Acid Cycle Function
Open accessAbstract
tricarboxylic acid cycle phosphoenolpyruvate carboxykinase phosphoenolpyruvate The oxidation of acetyl-CoA to CO2by the TCA1 cycle is the central process in energy metabolism. However, the TCA cycle also functions in biosynthetic pathways in which intermediates leave the cycle to be converted primarily to glucose, fatty acids, or non-essential amino acids. If TCA cycle anions are removed from the cycle they must be replaced to permit its continued function. This process is termed anaplerosis. Pyruvate carboxylase, which generates oxalacetate directly in the mitochondria, is the major anaplerotic enzyme. Conversely, 4- and 5-carbon intermediates enter the TCA cycle during the catabolism of amino acids. Because the TCA cycle cannot fully oxidize 4- and 5-carbon compounds, these intermediates must be removed from the cycle by a process termedcataplerosis. Cataplerosis may be linked to biosynthetic processes such as gluconeogenesis in the liver and kidney cortex, fatty acid synthesis in the liver, and glyceroneogenesis in adipose tissue. Cataplerotic enzymes present in many mammalian tissues include P-enolpyruvate carboxykinase (PEPCK), glutamate dehydrogenase, aspartate aminotransferase, and citrate lyase. In this review we have evaluated the roles of anaplerosis and cataplerosis in whole body metabolism. The expression anaplerotic sequences was a term used in biochemistry by Sir Hans Kornberg (1Kornberg H.L. Essays Biochem. 1966; 2: 1-31Crossref Scopus (359) Google Scholar) to describe a series of enzymatic reactions or pathways that replenish the pools of metabolic intermediates in the TCA cycle. These intermediates are critical for the functioning of the TCA cycle, the primary role of which is the oxidation of acetyl-CoA to carbon dioxide. The pool of TCA cycle intermediates is sufficient to sustain the oxidative carbon flux over a fairly wide range, so that during high energy consumption (e.g. exercise) or during lower energy consumption (e.g. fasting), there is not a large change in the pool size of TCA intermediates (2Graham T.E. Gibala M.J. Richter E.A. Galbo H. Kiens B. Saltin B. Skeletal Muscle Metabolism in Exercise and Diabetes. Plenum Press, New York1998: 271-286Google Scholar). However, in several physiological states, there is a large influx (anaplerosis) of 4- and 5-carbon intermediates into the TCA cycle. Because the TCA cycle cannot act as a carbon sink, anaplerosis must be coupled with the exit of intermediates from the cycle via cataplerosis. The importance of anaplerotic reactions for cellular metabolism is thus apparent. However, the coupling of this process with cataplerosis and the roles that both pathways play in the regulation of amino acid, glucose, and fatty acid metabolism have not been emphasized to a sufficient extent. The terms anaplerosis and cataplerosis describe reciprocal and correlative reactions involved in the function of the TCA cycle. The enzymatic steps in these processes have long been known, but the overall concept of a linkage between anaplerosis and cataplerosis should be underscored, because the balance between these two processes controls the entry and exit of TCA cycle anions. Anaplerotic and cataplerotic reactions are involved in the ultimate disposal of all metabolic intermediates. The metabolic role of anaplerosis and cataplerosis in amino acid metabolism varies with specific organs and is dependent on the nutritional/metabolic status of the individual. During feeding, the intestine is an important site of catabolism of enterally derived amino acids, whereas in the starved state amino acid catabolism occurs primarily in the kidney, liver, and muscle. The catabolism of amino acids produces gluconeogenic or ketogenic precursors (Table I). The disposal of gluconeogenic anions in the TCA cycle employs anaplerotic and cataplerotic pathways for their terminal oxidation. The only known pathway for the terminal oxidation of leucine is through acetoacetate to acetyl-CoA and subsequent oxidation in the TCA cycle. However, other amino acids also have for their disposal alternate ketogenic pathways for terminal oxidation. Thus, the ketogenic amino acids from proteolysis can be terminally oxidized in muscle, whereas the gluconeogenic amino acids are dependent upon anaplerosis and cataplerosis for conversion to glucose in the liver and kidney before oxidation to CO2 and H2O.Table IMetabolic fates of amino acids in the TCA cycle1. Amino acids converted to pyruvate Alanine, serine, glycine, threonine, cysteine, tryptophan2. Amino acids converted to oxaloacetate Aspartate, asparagine3. Amino acids converted to α-ketoglutarate Glutamate, glutamine, proline, histidine, arginine4. Amino acids converted to fumarate Phenylalanine, tyrosine5. Amino acids converted to succinyl-CoA Methionine, isoleucine, valine6. Amino acids converted to acetyl-CoA Leucine, isoleucine, lysine, phenylalanine, tyrosine, tryptophan, threonine Open table in a new tab The first reaction of the TCA cycle,
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“Pyruvate, derived from glucose, lactate, and amino acid sources, can function as a major anaplerotic source of OAA through the activity of the mitochondrial enzyme pyruvate carboxylase (PC) (37).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [37]
In the citing paper
“Cataplerosis of any TCA cycle intermediate requires compensatory input to sustain TCA cycle activity, a process termed “anaplerosis” (37).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [37]
In the citing paper
“Among the mitochondrial functions that may be relevant for white adipose tissue function are the anaplerotic generation of metabolic intermediates for fatty acid synthesis and esterification (159), the maintenance of a robust pathway for the folding and secretion of high abundance circulating proteins such as adiponectin (160), and interactions between mitochondrial function and components of the”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [159]
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Salminen, A., Haapasalo, A., Kauppinen, A., Kaarniranta, K., Soininen, H. S., & Hiltunen, M. O. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.001 · Cited by 107
“be metabolized to 2-oxoglutarate via anaplerotic glutamate pathway (Owen et al., 2002; Trofimova et al., 2012).”
BackgroundInfluentialPhannasil, P., Thuwajit, C., Warnnissorn, M., Wallace, J. C., MacDonald, M. J., & Jitrapakdee, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0129848 · Cited by 103
“Anaplerotic reactions are important to replenish the levels of TCA cycle intermediates upon their removal for biosynthetic purposes [9,28].”
BackgroundExploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)
Bruntz, R. C., Lane, A. N., Higashi, R. M., & Fan, T. W. ‐. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.776054 · Cited by 107
“Many cancer cells use anaplerosis to replenish intermediates that exit the Krebs cycle to support anabolic and/or anti-oxidative demands during cell proliferation (45).”
BackgroundLu, Y., Yao, D., & Chen, C. (2013) · Metabolites · doi:10.3390/metabo3040993 · Cited by 101
“The observed decrease in its level reflects the cataplerotic effects of type 1 diabetes [30].”
BackgroundTriheptanoin improves brain energy metabolism in patients with Huntington disease
Adanyeguh, I. M., Rinaldi, D., Henry, P., Caillet, S., Valabrègue, R., Dürr, A., & Mochel, F. (2015) · Neurology · doi:10.1212/wnl.0000000000001214 · Cited by 104
“Finally, triheptanoin may affect the glutamateglutamine cycling that is altered in HD(26) through the provision of Krebs cycle intermediates such as a-ketoglutarate, which undergo transamination for the synthesis of glutamate.(27) Newly developed techniques that have the potential to establish brain map of glutamate l…”
BackgroundNADPH and Glutathione Redox Link TCA Cycle Activity to Endoplasmic Reticulum Homeostasis
Gansemer, E. R., McCommis, K. S., Martino, M. R., King-McAlpin, A. Q., Potthoff, M. J., Finck, B. N., Taylor, E. B., & Rutkowski, D. T. (2020) · iScience · doi:10.1016/j.isci.2020.101116 · Cited by 102
“Yet, independent of diet content, feeding after a fast is sufficient to elicit ER stress in the liver (Gomez and Rutkowski, 2016; Oyadomari et al., 2008; Pfaffenbach et al., 2010) and to alter the extent of physical contacts between the ER and mitochondria (Theurey et al.”
BackgroundInfluentialPalmieri, E. M., Spera, I., Menga, A., Infantino, V., Porcelli, V., Iacobazzi, V., Pierri, C. L., Hooper, D. C., Palmieri, F., & Castegna, A. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.04.009 · Cited by 100
“In the cytoplasm citrate inhibits glycolysis while supporting lipid synthesis and the reduction of NADP [41,42].”
BackgroundDifferences between Human and Rodent Pancreatic Islets
MacDonald, M. J., Longacre, M. J., Stoker, S. W., Kendrick, M. A., Thonpho, A., Brown, L. J., Hasan, N. M., Jitrapakdee, S., Fukao, T., Hanson, M. S., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.241182 · Cited by 105
Salminen, A., Kauppinen, A., & Kaarniranta, K. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1978-z · Cited by 99
“, amino acid aminotransferases convert 2-oxoglutarate to glutamate and consequently glutamate can be metabolized to some other amino acids [29].”
BackgroundMalleable Mitochondrion of Trypanosoma brucei
Verner, Z., Basu, S., Benz, C., Dixit, S., Dobáková, E., Faktorová, D., Hashimi, H., Horáková, E., Huang, Z., Paris, Z., et al. (2015) · International review of cytology · doi:10.1016/bs.ircmb.2014.11.001 · Cited by 91
“Total yield of this set of reactions is one molecule of highenergy phosphate (GTP), two molecules of CO2, and four molecules of reduced cofactors (Owen et al., 2002).”
BackgroundSynthesis of Indomorphan Pseudo‐Natural Product Inhibitors of Glucose Transporters GLUT‐1 and ‐3
Ceballos, J., Schwalfenberg, M., Karageorgis, G., Reckzeh, E. S., Sievers, S., Ostermann, C., Pahl, A., Sellstedt, M., Nowacki, J., Corrales, M. A. C., et al. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201909518 · Cited by 98
Varman, A. M., He, L., Follenfant, R., Wu, W., Wemmer, S., Wrobel, S. A., Tang, Y., & Singh, S. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1606043113 · Cited by 95
“The anaplerotic/cataplerotic pathways play a significant role in regulating the flux of the tricarboxylic acid (TCA) cycle (44).”
BackgroundMakowka, A., Nichelmann, L., Schulze, D., Spengler, K., Wittmann, C., Forchhammer, K., & Gutekunst, K. (2020) · Molecular Plant · doi:10.1016/j.molp.2020.02.002 · Cited by 98
Cardiac anaplerosis in health and disease: food for thought
Rosiers, C. D., Labarthe, F., Lloyd, S. G., & Chatham, J. C. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr055 · Cited by 94
Abrego, J., Gunda, V., Vernucci, E., Shukla, S. K., King, R. J., Dasgupta, A., Goode, G. D., Murthy, D., Yu, F., & Singh, P. K. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.04.029 · Cited by 96
“As a parallel nutrient source, glutamine is essential for oxidative metabolism because it can be metabolized to generate alpha-ketoglutarate and enter the TCA cycle [27].”
BackgroundHepatic glucose sensing and integrative pathways in the liver
Oosterveer, M. H., & Schoonjans, K. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1505-z · Cited by 102
“To keep TCA cycle intermediates at a constant level, reactions that extract TCA metabolites for biosynthesis (cataplerotic reactions) are balanced by those that replenish TCA intermediates (anaplerotic reactions) [22].”
BackgroundThe multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit?
Abla, H., Sollazzo, M., Gasparre, G., Iommarini, L., & Porcelli, A. M. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.031 · Cited by 99
“bolic reprogramming is one of the hallmarks of cancer cells that use a series of anaplerotic reactions to replenish the TCA cycle intermediates [33].”
BackgroundKadhi, O. A., Melchini, A., Mithen, R. F., & Saha, S. (2017) · Journal of Analytical Methods in Chemistry · doi:10.1155/2017/5391832 · Cited by 94
“It encompasses a cyclic series of reactions that oxidises citrate to generate NADH (reduced form of nicotinamide adenine dinucleotide, NAD) and a series of metabolites that can be used for amino acid and lipid synthesis, as well as the regeneration of citrate through the condensation of acetyl CoA with oxaloacetate (F…”
BackgroundEnhancing itaconic acid production by Aspergillus terreus
Tevž, G., Benčina, M., & Legiša, M. (2010) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-010-2642-z · Cited by 94
“The expression ‘anaplerotic sequence’ is a term used in biochemistry to describe a series of enzymatic reactions or pathways that replenish the pool of metabolic intermediates of the TCA cycle (Owen et al. 2002).”
BackgroundThe TCA cycle as a bridge between oncometabolism and DNA transactions in cancer
Ciccarone, F., Vegliante, R., Leo, L. D., & Ciriolo, M. R. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.06.008 · Cited by 97
Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue
Samms, R. J., Zhang, G., He, W., Ilkayeva, O., Droz, B. A., Bauer, S. M., Stutsman, C., Pirro, V., Collins, K. A., Furber, E. C., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101550 · Cited by 93
“The TCA cycle is a central pathway linking the catabolism of energy substrates to the electron transport system [41,42].”
BackgroundRe-balancing cellular energy substrate metabolism to mend the failing heart
Glatz, J. F. C., Nabben, M., Young, M. E., Schulze, P. C., Taegtmeyer, H., & Luiken, J. J. F. P. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165579 · Cited by 93
“Although the role of anaplerosis is well recognized as a major biosynthetic pathway in liver [37], it is only beginning to be appreciated in heart [38,39].”
BackgroundChen, X., Sunkel, B. D., Wang, M., Kang, S., Wang, T., Gnanaprakasam, J. R., Liu, L., Cassel, T., Scott, D. A., Muñoz-Cabello, A. M., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abm8161 · Cited by 94
“The critical functions of the TCA cycle include producing energy through coupling with the oxidative phosphorylation and generating biosynthetic precursors through cataplerosis (11).”
BackgroundInfluentialMatsuzaki, F., Shimizu, M., & Wariishi, H. (2008) · Journal of Proteome Research · doi:10.1021/pr700617s · Cited by 93
Burch, J. S., Marcero, J. R., Maschek, J. A., Cox, J. E., Jackson, L. K., Medlock, A. E., Phillips, J. D., & Dailey, H. A. (2018) · Blood · doi:10.1182/blood-2018-01-829036 · Cited by 92
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Laufer, K., Røy, H., Jørgensen, B. B., & Kappler, A. A. (2016) · Applied and Environmental Microbiology · doi:10.1128/aem.01570-16 · Cited by 93
Wang, L., Wang, D., Zhang, T., Ma, Y., Tong, X., & Fan, H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1117548 · Cited by 100
“The Krebs cycle, also known as the TCA cycle, is the final common pathway for the oxidation of carbohydrates, fatty acids, and amino acids and is also a source of precursors for many other biological molecules, such as non-essential amino acids, nucleotide bases, and porphyrin (93, 94).”
BackgroundCarobbio, S., Ishihara, H., Fernández‐Pascual, S., Bartley, C., Martín-del-Río, R., & Maechler, P. (2004) · Diabetologia · doi:10.1007/s00125-003-1306-2 · Cited by 93
“Moreover, following an overnight fast, there is a net release of amino acids from skeletal muscle, glutamine being quantitatively most prominent [ 48 ].”
BackgroundUnique Metabolic Features of Stem Cells, Cardiomyocytes, and Their Progenitors
Gaspar, J. A., Doss, M. X., Hengstler, J. G., Cadenas, C., Hescheler, J., & Sachinidis, A. (2014) · Circulation Research · doi:10.1161/circresaha.113.302021 · Cited by 92
“cycle for biosynthetic purposes, they must be replenished—a process termed anaplerosis.(47) Conversely, reactions that re-”
BackgroundTissue specificity of mitochondrial glutamate pathways and the control of metabolic homeostasis
Frigerio, F., Casimir, M., Carobbio, S., & Maechler, P. (2008) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2008.04.031 · Cited by 90
Czyż, D. M., Willett, J. W., & Crosson, S. (2017) · Journal of Bacteriology · doi:10.1128/jb.00227-17 · Cited by 87
“Most amino acids can be metabolized to enter the TCA cycle through anaplerotic 119 reactions (11).”
BackgroundChicco, A. J., Le, C. H., Gnaiger, E., Dreyer, H. C., Muyskens, J. B., D’Alessandro, A., Nemkov, T. G., Hocker, A. D., Prenni, J. E., Wolfe, L. M., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000470 · Cited by 88
“Protein catabolism may be protective in hypoxia for several reasons (27), but also requires myocytes to balance accumulating anaplerotic carbons and amino nitrogen with cataplerotic reactions to rid the cell of ammonia while meeting cellular energy demands (51).”
BackgroundThe long and winding road of cardiomyocyte maturation
Maroli, G., & Braun, T. W. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa159 · Cited by 89
Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver
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“It replaces the metabolites that are removed from the TCA cycle for the biosynthesis of fatty acids, nucleotides, and proteins allowing the TEFF cells to maintain the integrity of the TCA cycle function (60).”
BackgroundAutophagy in adipose tissue biology
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Gómez-Valadés, A. G., Vidal‐Alabró, A., Molas, M., Boada, J., Bermúdez, J., Bartrons, R., & Perales, J. C. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.08.026 · Cited by 86
“PEPCK is also involved in the control of acid–base in the kidney [4,5], glyceroneogenesis in adipose tissue [5,6], and glutamine metabolism in small intestine [5,7].”
BackgroundRoles of pyruvate carboxylase in human diseases: from diabetes to cancers and infection
Lao-On, U., Attwood, P. V., & Jitrapakdee, S. (2018) · Journal of Molecular Medicine · doi:10.1007/s00109-018-1622-0 · Cited by 85
Integrative proteomics and phosphoproteomics in pulmonary arterial hypertension
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“and indicate an anaplerotic shift, which is the replenishment of TCA cycle intermediates diverted to various biosynthetic pathways [22], in this case by the increased utilization of Gln.”
Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch
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Metadata
- Authors
- Owen, O. E., Kalhan, S. C., & Hanson, R. W.
- Affiliations
- MetroHealth Medical Center (US)
- Corresponding author
- Owen, Oliver E.
- ORCID
- Kalhan, Satish C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 34
- Pages
- 30409-30412
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2134294998
- Cited by
- 1,172
- References
- 21
- Citations by year
- 2026: 51 · 2025: 73 · 2024: 72 · 2023: 71 · 2022: 87 · 2021: 108 · 2020: 101 · 2019: 84 · 2018: 67 · 2017: 67 · 2016: 61 · 2015: 50 · 2014: 49 · 2013: 27 · 2012: 38
- FWCI
- 6.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-58620, R01DK058620)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD11089)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Keywords
- anaplerosis, cataplerosis, TCA cycle, TCA cycle intermediates, pyruvate carboxylase, oxaloacetate, phosphoenolpyruvate carboxykinase, gluconeogenesis, fatty acid synthesis, glyceroneogenesis, amino acid catabolism, glutamate dehydrogenase
- MeSH terms
- Adipose Tissue, Amino Acids, Animals, Citric Acid Cycle, Gluconeogenesis, Glutamine, Humans, Intestine, Small, Kidney, Triglycerides, Muscle, Skeletal
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