The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
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,
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Liver and kidney metabolism during prolonged starvation
Owen, O. E., Felig, P., Morgan, A. P., Wahren, J., & Cahill, G. F. (1969) · Journal of Clinical Investigation · doi:10.1172/jci106016 · Cited by 871
Amino acid metabolism during prolonged starvation
Felig, P., Owen, O. E., Wahren, J., & Cahill, G. F. (1969) · Journal of Clinical Investigation · doi:10.1172/jci106017 · Cited by 729
The Production and Release of Glycerol by Adipose Tissue Incubated in Vitro
Vaughan, M. M. (1962) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)70821-7 · Cited by 428
Izenstein, B. Z. (1996) · JAMA · doi:10.1001/jama.1996.03530350062036 · Cited by 357
Reeds, P. J., Fjeld, C. R., & Jahoor, F. (1994) · Journal of Nutrition · doi:10.1093/jn/124.6.906 · Cited by 338
Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans
Jungas, R. L., Halperin, M. L., & Brosnan, J. T. (1992) · Physiological Reviews · doi:10.1152/physrev.1992.72.2.419 · Cited by 309
The metabolic fates of amino acids and the formation of glutamine in skeletal muscle.
Chang, T. W., & Goldberg, A. L. (1978) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)34855-x · Cited by 274
Tricarboxylic acid cycle intermediates in human muscle during prolonged exercise
Sahlin, K., Katz, A., & Broberg, S. (1990) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1990.259.5.c834 · Cited by 271
GLUTAMINE AS SOURCE MATERIAL OF URINARY AMMONIA
Slyke, D. D. V., Phillips, R. A., Hamilton, P., Archibald, R. M., Futcher, P. H., & Hiller, A. (1943) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)72173-x · Cited by 208
Garber, A. J., Karl, I. E., & KIPNIS, D. M. (1976) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)33859-0 · Cited by 207
Flagged first, then by citations
Research works printed but not linked: 6
- Kornberg, 1966, Essays Biochem., 2, 1
- Castillo, 1991, Am. J. Physiol., 261, E598
- Gibala, 1998, Am. J. Physiol., 275, E235
- Matthews, 1993, Am. J. Physiol., 264, E848
- Haisch, 2000, Am. J. Physiol., 278, E593
- Devapatla, 2002, Pediatr. Res., 51, 286A
Cited by
Sorted by citations
Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation
Lunt, S. Y., & Vander Heiden, M. G. (2011) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-092910-154237 · Cited by 3,057
“Amino acids enter the TCA cycle via pyruvate, acetyl-CoA, acetoacetylCoA, α-ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate (Owen et al 2002, Voet & Voet 2004).”
Fundamentals of Cancer Metabolism
DeBerardinis, R. J., & Chandel, N. S. (2016) · Science Advances · doi:10.1126/sciadv.1600200 · Cited by 3,013
“Their utilization in biosynthetic pathways requires that carbon be resupplied to the cycle so that intermediate pools aremaintained; pathways that “refill” the cycle are termed anaplerotic pathways, and they generate TCA cycle intermediates that can enter the cycle at sites other than acetyl-CoA (coenzymeA) (14).”
BackgroundDiet Drives Convergence in Gut Microbiome Functions Across Mammalian Phylogeny and Within Humans
Muegge, B. D., Kuczynski, J., Knights, D., Clemente, J. C., González, A., Fontana, L., Henrissat, B., Knight, R., & Gordon, J. I. (2011) · Science · doi:10.1126/science.1198719 · Cited by 1,988
“When tricarboxylic acid cycle intermediates are withdrawn for biosynthesis, they are replenished by converting PEP and pyruvate directly to OAA (12).”
InfluentialMetabolic reprogramming in macrophages and dendritic cells in innate immunity
Kelly, B., & O'Neill, L. A. (2015) · Cell Research · doi:10.1038/cr.2015.68 · Cited by 1,876
Glutamine addiction: a new therapeutic target in cancer
Wise, D. R., & Thompson, C. B. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.05.003 · Cited by 1,770
Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics
Puchalska, P., & Crawford, P. A. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2016.12.022 · Cited by 1,682
“Acetyl-CoA allosterically activates (1) pyruvate carboxylase (PC), thereby activating a metabolic control mechanism that augments anaplerotic entry of metabolites into the TCA cycle (Owen et al., 2002; Scrutton and Utter, 1967), and (2) pyruvate dehydrogenase kinase, which phosphorylates and inhibits pyruvate dehydrog…”
BackgroundN-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology
MOFFETT, J., Ross, B., Arun, P., Madhavarao, C. N., & Namboodiri, A. M. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.12.003 · Cited by 1,443
“Two important cataplerotic enzymes that help remove excess TCA intermediates are aspartate aminotransferase and citrate lyase (Owen et al., 2002).”
BackgroundLinks between metabolism and cancerPreprint
Dang, C. V. (2012) · Genes & Development · doi:10.1101/gad.189365.112 · Cited by 1,021
“Glutamine released into the circulation is used by the kidney for gluconeogenesis by conversion to glutamate and then to aKG, which ends up as oxaloacetate and phosphoenol pyruvate for glucose synthesis (Owen et al. 2002).”
Regulation of pyruvate metabolism and human disease
Gray, L. R., Tompkins, S. C., & Taylor, E. B. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1539-2 · Cited by 983
“For example, α-ketoglutarate is a key intermediate for the biogenesis of glutamine, glutamate, arginine, and proline, while oxaloacetate is used to generate aspartate and asparagine [119].”
BackgroundPatra, K. C., Wang, Q., Bhaskar, P. T., Miller, L. L., Wang, Z., Wheaton, W. W., Chandel, N. S., Laakso, M., Muller, W. J., Allen, E. L., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.06.014 · Cited by 884
“Corresponding reductions in citrate abundance, derived from Glc, and TCA cycle intermediates, derived from Gln, could be both a cause and a consequence of reduced Gln incorporation, as anaplerosis and cataplerosis are always tightly matched to maintain TCA cycle carbon balance (Owen et al., 2002).”
BackgroundAn Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma
Hakimi, A. A., Reznik, E., Lee, C., Creighton, C. J., Brannon, A. R., Luna, A., Aksoy, B. A., Liu, E. M., Shen, R., Lee, W., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2015.12.004 · Cited by 815
“We next investigated the TCA cycle, which plays central roles in both ATP production through oxidation of acetyl-CoA to CO2 and the production of biosynthetic precursors (Owen et al., 2002).”
The role of mitochondria in metabolism and cell death
Vakifahmetoglu-Norberg, H., Ouchida, A. T., & Norberg, E. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.11.088 · Cited by 754
Yang, C., Ko, B., Hensley, C. T., Jiang, L., Wasti, A. T., Kim, J., Sudderth, J., Calvaruso, M. A., Lumata, L., Mitsche, M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.09.025 · Cited by 679
“These OAA-producing pathways, termed anaplerosis, enable the TCA cycle to function as a biosynthetic pathway as opposed to a purely bioenergetic one (Owen et al., 2002).”
BackgroundSuccinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
King, A., Selak, M. A., & Gottlieb, E. (2006) · Oncogene · doi:10.1038/sj.onc.1209594 · Cited by 672
“Moreover, enhanced glucose breakdown provides building blocks for the synthesis of nucleotides (via the pentose phosphate pathway), and amino and fatty acids (from glycolytic and TCA cycle intermediates) (Figure 1) (Owen et al., 2002).”
BackgroundThe Energy Sensor AMPK Regulates T Cell Metabolic Adaptation and Effector Responses In Vivo
Blagih, J., Coulombe, F., Vincent, E. E., Dupuy, F., Galicia-Vázquez, G., Yurchenko, E., Raissi, T. C., van der Windt, G. J. W., Viollet, B., Pearce, E. L., et al. (2015) · Immunity · doi:10.1016/j.immuni.2014.12.030 · Cited by 679
“Glucose-derived pyruvate is an important source of acetylCoA, which is a key carbon input into the TCA cycle (Owen et al., 2002).”
BackgroundMetabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma
Du, D., Liu, C., Qin, M., Zhang, X., Xi, T., Yuan, S., Hao, H., & Xiong, J. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.09.019 · Cited by 665
Sarcopenia from mechanism to diagnosis and treatment in liver disease
Dasarathy, S., & Merli, M. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.07.040 · Cited by 608
“substrates to generate a ketoglutarate (aKG) and ammonia in most tissues to maintain sufficient concentrations of the tricarboxylic acid (TCA) cycle intermediates [94].”
Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells
Jones, C. L., Stevens, B. M., D'Alessandro, A., Reisz, J. A., Culp-Hill, R., Nemkov, T., Pei, S., Khan, N., Adane, B., Ye, H., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.10.005 · Cited by 585
Lee, S. Y., Jeong, E. K., Ju, M. K., Jeon, H. M., Kim, M. Y., Kim, C. H., Park, H. G., Han, S. I., & Kang, H. S. (2017) · Molecular Cancer · doi:10.1186/s12943-016-0577-4 · Cited by 592
The role of mitochondria in the pathogenesis of type 2 diabetes
Patti, M.-E., & Corvera, S. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0027 · Cited by 551
“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 adiponec…”
BackgroundFasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1
Rodgers, J. T., & Puigserver, P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702509104 · Cited by 466
Marin-Valencia, I., Yang, C., Mashimo, T., Cho, S., Baek, H., Yang, X.-L., Rajagopalan, K. N., Maddie, M., Vemireddy, V., Zhao, Z., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.05.001 · Cited by 529
“Anaplerosis, the process by which the CAC generates excess intermediates for neurotransmitter synthesis in the brain and for macromolecular synthesis during cell growth (Owen et al., 2002), also contributed significantly to overall tumor CAC activity in both compartments (Figure S3F).”
BackgroundSauer, U., & Eikmanns, B. J. (2004) · FEMS Microbiology Reviews · doi:10.1016/j.femsre.2004.11.002 · Cited by 538
“A catabolic function of PEP carboxykinase has recently been also proposed for mammalian cells degrading amino acids [91].”
BackgroundRegulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535
“PC-derived OAA can either contribute to the TCA cycle or serve as a substrate for phosphoenolpyruvate carboxykinase, which catalyzes the decarboxylation of OAA to phosphoenolpyruvic acid in the gluconeogenic pathway (37).”
BackgroundInfluentialPyruvate carboxylase is required for glutamine-independent growth of tumor cells
Cheng, T., Sudderth, J., Yang, C., Mullen, A. R., Jin, E. S., Matés, J. M., & DeBerardinis, R. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1016627108 · Cited by 475
“These OAA-generating pathways are termed anaplerosis (6).”
Structure and function of biotin-dependent carboxylases
Tong, L. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1096-0 · Cited by 492
“PC has an important anaplerotic role, replenishing the intermediates of the tricarboxylic acid (TCA) cycle that have been withdrawn for the biosynthesis of glucose, fatty acids, amino acids and other molecules [244].”
Wilson-Fritch, L., Burkart, A., Bell, G., Mendelson, K., Leszyk, J., Nicoloro, S., Czech, M., & Corvera, S. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.3.1085-1094.2003 · Cited by 459
“The finding that pyruvate carboxylase is highly overexpressed upon adipose conversion is consistent with an important role of glyceroneogenesis in tryglyceride formation (19).”
BackgroundAMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function
Dugan, L. L., You, Y.-H., Ali, S. S., Diamond-Stanic, M. K., Miyamoto, S., Declèves, A., Andreyev, A. Y., Quach, T., Ly, S., Shekhtman, G., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66218 · Cited by 457
“Mitochondria respond to the caloric availability of the cell by following 2 major pathways: anaplerosis or cataplerosis (30).”
Structure, mechanism and regulation of pyruvate carboxylase
Jitrapakdee, S., Maurice, M. S., Rayment, I., Cleland, W. W., Wallace, J. C., & Attwood, P. V. (2008) · Biochemical Journal · doi:10.1042/bj20080709 · Cited by 470
Krebs cycle Reborn in macrophage immunometabolism
Ryan, D. G., & O'Neill, L. A. J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-081619-104850 · Cited by 444
“For example, oxaloacetate is an intermediate for the synthesis of glucose from noncarbohydrate precursors, a process termed gluconeogenesis (6).”
BackgroundInfluentialKetone body metabolism and cardiovascular disease
Cotter, D. G., Schugar, R. C., & Crawford, P. A. (2013) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00646.2012 · Cited by 459
The chemistry and biology of ferroptosis
Stockwell, B. R., & Jiang, X. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.03.013 · Cited by 429
“Ferroptosis has also been implicated as a pathological contributor to neurodegenerative diseases (DeGregorio-Rocasolano et al., 372 Cell Chemical Biology 27, April 16, 2020 2019; Pena-Bautista et al., 2019).”
BackgroundMitochondrial calcium exchange in physiology and disease
Garbincius, J. F., & Elrod, J. W. (2021) · Physiological Reviews · doi:10.1152/physrev.00041.2020 · Cited by 427
Diamond, D. L., Syder, A. J., Jacobs, J., Sorensen, C. M., Walters, K., Proll, S. C., McDermott, J., Gritsenko, M. A., Zhang, Q., Zhao, R., et al. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000719 · Cited by 429
“In order to ensure continued TCA cycle function in macromolecular biosynthesis, cells must replenish the pools of metabolic intermediates (anaplerosis) depleted during lipid, protein, and nucleic acid synthesis [36,39].”
BackgroundSatapati, S., Sunny, N. E., Kucejova, B., Fu, X., He, T. T., Méndez-Lucas, A., Shelton, J. M., Perales, J. C., Browning, J. D., & Burgess, S. C. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m023382 · Cited by 407
Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver
Satapati, S., Kucejová, B., Duarte, J. A. G., Fletcher, J. A., Reynolds, L., Sunny, N. E., He, T., Nair, L. A., Livingston, K. A., Fu, X., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci82204 · Cited by 403
“First, anaplerosis/cataplerosis and substrate oxidation both produce and require OAA (1, 8).”
BackgroundInfluentialInvestigating mitochondrial redox state using NADH and NADPH autofluorescence
Blacker, T. S., & Duchen, M. R. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.08.010 · Cited by 406
“While this process may classically be viewed as a catabolic prelude to ATP generation by aerobic respiration, the large array of intermediates involved serve as important biosynthetic precursors [34], including for the synthesis of non-essential amino acids and fatty acids [47].”
BackgroundLiver glucose metabolism in humans
Adeva-Andany, M. M., Pérez-Felpete, N., Fernández-Fernández, C., Donapetry-García, C., & Pazos-García, C. (2016) · Bioscience Reports · doi:10.1042/bsr20160385 · Cited by 372
“Several reactions in the TCA cycle provide NADH and FADH 2 that are subsequently oxidized in the mitochondrial respiratory chain to produce ATP [53].”
BackgroundNADPH-generating systems in bacteria and archaea
Spaans, S. K., Weusthuis, R. A., John van der, O. O. S. T., & Kengen, S. W. M. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00742 · Cited by 389
“This node represents the metabolic link between glycolysis/gluconeogenesis and the TCA cycle (Owen et al., 2002; Sauer and Eikmanns, 2005).”
BackgroundJudge, A., & Dodd, M. S. (2020) · Essays in Biochemistry · doi:10.1042/ebc20190041 · Cited by 421
Mitochondrial dysfunction in white adipose tissue
Kusminski, C. M., & Scherer, P. E. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.06.004 · Cited by 382
“To sustain lipogenesis, mitochondria provide key intermediates for the synthesis of TGs through the actions of pyruvate carboxylase [53].”
Rice, C. M., Davies, L. C., Subleski, J. J., Maio, N., Gonzalez-Cotto, M., Andrews, C., Patel, N. L., Palmieri, E. M., Weiss, J. M., Lee, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07505-2 · Cited by 358
Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony
Herman, M. A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29027 · Cited by 360
Transcript Profiling of the Anoxic Rice Coleoptile
Lasanthi-Kudahettige, R., Magneschi, L., Loreti, E., Gonzali, S., Licausi, F., Novi, G., Beretta, O., Vitulli, F., Alpi, A., & Pierdomenico Perata, A. (2007) · PLANT PHYSIOLOGY · doi:10.1104/pp.106.093997 · Cited by 351
Citrate anticoagulation for continuous venovenous hemofiltration*
Straaten, H. M. O., Bosman, R. J., Koopmans, M., van der Voort, P. H. J., Wester, J. P., van der Spoel, J. I., Dijksman, L. M., & Zandstra, D. F. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181953c5e · Cited by 327
“Substrate availability is a crucial regulator of the citric acid cycle, a central pathway recovering energy and maintaining redox state (37).”
BackgroundSalabei, J. K., Gibb, A., & Hill, B. G. (2014) · Nature Protocols · doi:10.1038/nprot.2014.018 · Cited by 333
Metabolic changes in tumor cells and tumor-associated macrophages: A mutual relationship
Netea-Maier, R. T., Smit, J. W. A., & Netea, M. G. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.10.037 · Cited by 333
“Upon increased nutrient diversion to the TCA cycle, intermediates of the TCA such as citrate can also be used for production of lipids and amino acids [27,29].”
Goodson, W. H., Lowe, L. J., Carpenter, D. O., Gilbertson, M., Ali, A. M., Salsamendi, A. L. D. C., Lasfar, A., Carnero, A., Azqueta, A., Amedei, A., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv039 · Cited by 336
“Amino acid metabolism—particularly glutamine and serine metabolism—also has well-established roles in cancer (364–366), providing additional potential targets for study that include 3-phosphoglycerate dehydrogenase (346,365,367,368) and cellular transaminase coupling mechanisms.”
BackgroundAchieving Life through Death: Redox Biology of Lipid Peroxidation in Ferroptosis
Bayır, H., Anthonymuthu, T. S., Tyurina, Y. Y., Patel, S. J., Amoscato, A. A., Lamade, A. M., Yang, Q., Vladimirov, G. K., Philpott, C. C., & Kagan, V. E. (2020) · Cell chemical biology · doi:10.1016/j.chembiol.2020.03.014 · Cited by 324
“Both GDH and TAs are considered as cataplerotic enzymes forming products necessary for removing TCA cycle intermediates (Owen et al., 2002).”
BackgroundDysregulated metabolism contributes to oncogenesis
Hirschey, M. D., DeBerardinis, R. J., Diehl, A. M., Drew, J. E., Frezza, C., Green, M. F., Jones, L. W., Ko, Y. H., Le, A., Lea, M. A., et al. (2015) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.10.002 · Cited by 316
“as a source of precursors for macromolecular synthesis in addition to generating reducing equivalents for oxidative phosphorylation [81].”
Resurgence of Serine: An Often Neglected but Indispensable Amino Acid
Kalhan, S. C., & Hanson, R. W. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.357194 · Cited by 312
“The details of the pathway of cataplerosis have been reviewed previously (39, 40).”
MethodGlucose metabolism and cardiac hypertrophy
Kolwicz, S. C., & Tian, R. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr071 · Cited by 302
“supply carbon-based substrates to the tricarboxylic acid (TCA) cycle, a process termed ‘anaplerosis’.(35) In particular, pyruvate can”
BackgroundEight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism
Walsh, C. T., Tu, B. P., & Tang, Y. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00510 · Cited by 315
Inflammasomes on the Crossroads of Innate Immune Recognition and Metabolic Control
Próchnicki, T., & Latz, E. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.018 · Cited by 302
The functional roles of TCA cycle metabolites in cancer
Eniafe, J., & Jiang, S. (2021) · Oncogene · doi:10.1038/s41388-020-01639-8 · Cited by 289
“Moreover, the intermediates of the TCA cycle are also often depleted to fuel other anabolic processes, including gluconeogenesis and amino acids biosynthesis [1].”
BackgroundMitochondrial pyruvate transport: a historical perspective and future research directions
McCommis, K. S., & Finck, B. N. (2015) · Biochemical Journal · doi:10.1042/bj20141171 · Cited by 277
“Although the PDH reaction is used predominantly for ATP production, the PC reaction is used for the production and replenishment of TCA cycle intermediates, which is known as anaplerosis [60].”
MethodPhosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis
Yu, S., Meng, S., Xiang, M., & Ma, H. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101257 · Cited by 277
“After breaking down and entering TCA, amino acid products are further converted into PEP catalyzed by PCK and fed into the serine biosynthetic pathway [27].”
BackgroundMetabolic adaptation in hypoxia and cancer
Paredes, F., Williams, H. C., & Martín, A. S. (2021) · Cancer Letters · doi:10.1016/j.canlet.2020.12.020 · Cited by 276
“Pyruvate, through anaplerotic reactions, may contribute carbon to these synthetic activities [101].”
BackgroundLuukkonen, P. K., Dufour, S., Lyu, K., Zhang, X., Hakkarainen, A., Lehtimäki, T. E., Cline, G. W., Petersen, K. F., Shulman, G. I., & Yki‐Järvinen, H. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922344117 · Cited by 261
Ferroptosis and its emerging roles in cardiovascular diseases
Li, N., Jiang, W., Wang, W., Xiong, R., Wu, X., & Geng, Q. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105466 · Cited by 256
Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis
Ritterhoff, J., Young, S., Villet, O. M., Shao, D., Neto, F. C., Bettcher, L., Hsu, Y. A., Kolwicz, S. C., Raftery, D., & Tian, R. (2019) · Circulation Research · doi:10.1161/circresaha.119.315483 · Cited by 229
Glutamine Metabolism in Cancer
Li, T., & Le, A. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-77736-8_2 · Cited by 242
Harfmann, B. D., Schroder, E. A., Kachman, M. T., Hodge, B. A., Zhang, X., & Esser, K. A. (2016) · Skeletal Muscle · doi:10.1186/s13395-016-0082-x · Cited by 231
“In healthy muscle, pyruvate generated from glycolysis may enter the TCA cycle as acetyl CoA at oxaloacetate and then the TCA cycle proceeds [23].”
BackgroundDetoxification mechanisms of honey bees (Apis mellifera) resulting in tolerance of dietary nicotine
du Rand, E. E., Smit, S., Beukes, M., Apostolides, Z., Pirk, C. W. W., & Nicolson, S. W. (2015) · Scientific Reports · doi:10.1038/srep11779 · Cited by 231
Mitochondrial dysfunction in pancreatic β cells
Supale, S., Li, N., Brun, T., & Maechler, P. (2012) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2012.06.002 · Cited by 247
Carboxylases in Natural and Synthetic Microbial Pathways
Erb, T. J. (2011) · Applied and Environmental Microbiology · doi:10.1128/aem.05702-11 · Cited by 231
Grasso, D., Zampieri, L. X., Capelôa, T., de Velde, J. A. V., & Sonveaux, P. (2020) · Cell Stress · doi:10.15698/cst2020.06.221 · Cited by 239
Regulation of Tumor Progression by Programmed Necrosis
Lee, S. Y., Ju, M. K., Jeon, H. M., Jeong, E. K., Lee, Y. J., Kim, C. H., Park, H. G., Han, S. I., & Kang, H. S. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/3537471 · Cited by 238
Serine Catabolism Feeds NADH when Respiration Is Impaired
Yang, L., García‐Cañaveras, J. C., Chen, Z., Wang, L., Liang, L., Jang, C., Mayr, J. A., Zhang, Z., Ghergurovich, J. M., Zhan, L., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.02.017 · Cited by 216
“Accordingly, there has been extensive research on NADH sources in different physiological and pathological contexts (Chen et al., 2018; Gaude et al., 2018; Guarente, 2008; McKenna et al., 2006; Owen et al., 2002; Solaini et al., 2010; Yang et al., 2014; Yaniv et al., 2013).”
BackgroundCunnane, S. C., Courchesne‐Loyer, A., Vandenberghe, C., St‐Pierre, V., Fortier, M., Hennebelle, M., Croteau, É., Bocti, C., Fülöp, T., & Castellano, C. (2016) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2016.00053 · Cited by 224
Zdzisińska, B., Żurek, A., & Kandefer-Szerszeń, M. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-016-0406-x · Cited by 221
“…to oxidative decarboxylation of AKG and formation of succinyl-CoA, while in the case of an increased concentration of NADH and a shortage of NAD?, reductive transamination of AKG takes place with the participation of glutamate dehydrogenase, leading to formation of glutamate (Owen et al. 2002).”
BackgroundThe Mitochondrion as an Emerging Therapeutic Target in Cancer
Roth, K. G., Mambetsariev, I., Kulkarni, P., & Salgia, R. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.06.009 · Cited by 219
Chakravarty, K., Cassuto, H., Reshef, L., & Hanson, R. W. (2005) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409230590935479 · Cited by 223
Cancer metabolism in space and time: Beyond the Warburg effect
Danhier, P., Bański, P., Payen, V. L., Grasso, D., Ippolito, L., Sonveaux, P., & Porporato, P. E. (2017) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2017.02.001 · Cited by 230
“This leads to a situation where more ATP is used and cataplerosis provides a constant out fl ow of intermediates [14,15].”
Liu, M., Jin, L., Sun, S.-J., Liu, P., Feng, X., Cheng, Z., Liu, W., Guan, K., Shi, Y., Yuan, H., et al. (2018) · Oncogene · doi:10.1038/s41388-017-0070-6 · Cited by 217
“highly active in liver cells and their balance is critical for the functioning of TCA cycle [12].”
PCK1 and PCK2 as candidate diabetes and obesity genes
BEALE, E. G., Harvey, B. J., & Forest, C. D. (2007) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-007-0025-6 · Cited by 209
“Cataplerosis and anaplerosis are the removal and addition of Citric Acid Cycle intermediates, respectively [15].”
BackgroundFrom OCR and ECAR to energy: Perspectives on the design and interpretation of bioenergetics studies
Schmidt, C. A., Fisher‐Wellman, K. H., & Neufer, P. D. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101140 · Cited by 206
Hakimi, P., Yang, J., Casadesús, G., Massillon, D., Tolentino‐Silva, F., Nye, C. K., Cabrera, M. E., Hagen, D., Utter, C. B., Baghdy, Y., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706127200 · Cited by 200
Rose, J., Brian, C., Pappa, A., Panayiotidis, M. I., & Franco, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.536682 · Cited by 196
Wnt/Snail Signaling Regulates Cytochrome c Oxidase and Glucose Metabolism
Lee, S. Y., Jeon, H. M., Ju, M. K., Kim, C. H., Yoon, G., Han, S. I., Park, H. G., & Kang, H. S. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0006 · Cited by 197
“To support cell proliferation, tumor cells also activate a process termed anaplerosis, which replenishes the precursors that are extracted from the tricarboxylic acid (TCA) cycle by cataplerosis (16).”
Fischer, G. M., Gopal, Y. N. V., McQuade, J. L., Peng, W., DeBerardinis, R. J., & Davies, M. A. (2017) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12661 · Cited by 200
Metabolism in Pulmonary Hypertension
Xu, W., Janocha, A. J., & ERZURUM, S. C. (2021) · Annual Review of Physiology · doi:10.1146/annurev-physiol-031620-123956 · Cited by 194
Ins and outs of the TCA cycle: the central role of anaplerosis
Inigo, M., Deja, S., & Burgess, S. C. (2021) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-120420-025558 · Cited by 189
The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis
Catalina-Rodriguez, O., Kolukula, V. K., Tomita, Y. A., Preet, A., Palmieri, F., Wellstein, A., Byers, S. W., Giaccia, A. J., Glasgow, E. F., Albanese, C., et al. (2012) · Oncotarget · doi:10.18632/oncotarget.714 · Cited by 190
“Interestingly, impairment of CIC activity also re-wires the metabolism towards glycolysis, either as a consequence of mitochondrial dysfunction (the Warburg effect) or due to the lowered concentration of citrate that enhances PFK1 activity (see scheme in Figure 1A). the ability of cIc to restrain the glycolytic addict…”
BackgroundInfluentialGlyceroneogenesis Is the Dominant Pathway for Triglyceride Glycerol Synthesis in Vivo in the Rat
Nye, C. K., Hanson, R. W., & Kalhan, S. C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804393200 · Cited by 182
Long, Y. C., Cheng, Z., Copps, K. D., & White, M. F. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00983-10 · Cited by 183
“Third, elevated lactate release from MDKO skeletal muscle diminishes pyruvate availability for the synthesis of oxaloacetate—a critical anaplerotic pathway to replenish the TCA cycle (47) (Fig.”
BackgroundBernard, K. F., Logsdon, N. J., Benavides, G. A., Sanders, Y. Y., Zhang, J., Darley-Usmar, V. M., & Thannickal, V. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.000444 · Cited by 181
“Anaplerotic reactions supply the TCA cycle with metabolites to support the production of reducing equivalents for oxidative phosphorylation (OXPHOS) and anabolic carbons for biosynthesis (15, 16).”
BackgroundGlucose Metabolism Heterogeneity in Human and Mouse Malignant Glioma Cell Lines
Griguer, C. E., Oliva, C. R., & Gillespie, G. Y. (2005) · Journal of Neuro-Oncology · doi:10.1007/s11060-004-6404-6 · Cited by 178
“Substrate level phosphorylation such as glycolysis also contributes a limited amount of ATP to the cellular energy pool [3].”
BackgroundBurgess, S. C., Hausler, N., Merritt, M. E., Jeffrey, F. M. H., Storey, C. J., Milde, A., Koshy, S., Lindner, J., Magnuson, M. A., Malloy, C. R., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407120200 · Cited by 178
Metabolic reprogramming and metabolic dependency in T cells
Wang, R., & Green, D. R. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01155.x · Cited by 180
“Glutamine is not only an important nitrogen and carbon donor for the synthesis of many other amino acids but also a major carbon resource for a-ketoglutarate (a-KG), an anapleurotic substrate of the TCA cycle (11).”
BackgroundThe evolutionary benefit of insulin resistance
Soeters, M. R., & Soeters, P. B. (2012) · Clinical Nutrition · doi:10.1016/j.clnu.2012.05.011 · Cited by 176
Gershman, B., Puig, Ó., Hang, L., Peitzsch, R. M., Tatar, M., & Garofalo, R. S. (2006) · Physiological Genomics · doi:10.1152/physiolgenomics.00061.2006 · Cited by 174
“The TCA cycle also serves a biosynthetic function in a process described as cataplerosis where four- and five-chain carbon skeletons are removed from the TCA cycle to be converted to glucose, fatty acids, or nonessential amino acids (44).”
BackgroundNutrition and Muscle in Cirrhosis
Anand, A. C. (2017) · Journal of Clinical and Experimental Hepatology · doi:10.1016/j.jceh.2017.11.001 · Cited by 182
Metabolic remodeling of white adipose tissue in obesity
Cummins, T. D., Holden, C. R., Sansbury, B. E., Gibb, A., Shah, J., Zafar, N., Tang, Y., Hellmann, J. L., Rai, S. N., Spite, M. R., et al. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00271.2013 · Cited by 176
“This decrease in pdk4 could potentially promote glyceroneogenic formation of G3P (8) via cataplerosis (45).”
BackgroundDiakos, N., Navankasattusas, S., Abel, E. D., Rutter, J. P., McCreath, L., Ferrin, P. C., McKellar, S. H., Miller, D. V., Park, S., Richardson, R. S., et al. (2016) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2016.06.009 · Cited by 169
“In addition to their putative role in protein synthesis, we believe that amino acids are also used as metabolic substrates in TCA cycle anaplerosis or by being transformed to fatty acids through removal (cataplerosis) of TCA cycle intermediates (29).”
Davuluri, G., Allawy, A., Thapaliya, S., Rennison, J. H., Singh, D., Kumar, A., Sandlers, Y. I., Wagoner, D. R. V., Flask, C. A., Hoppel, C. L., et al. (2016) · The Journal of Physiology · doi:10.1113/jp272796 · Cited by 177
“Lower TCA cycle intermediates, specifically αKG, can lower oxidative phosphorylation and ATP synthesis and only small increases are required to meet cellular energy needs (Sahlin et al. 1990; Owen et al. 2002).”
BackgroundAltered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques
Tomas, L., Edsfeldt, A., Mollet, I. G., Matic, L. P., Prehn, C. P., Adamski, J., Paulsson‐Berne, G., Hedin, U., Nilsson, J. Å., Bengtsson, E., et al. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy124 · Cited by 168
Vetterli, L., Brun, T., Giovannoni, L., Bosco, D., & Maechler, P. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.176842 · Cited by 170
Simoes, R. V., Serganova, I. S., Kruchevsky, N., Leftin, A., Shestov, A. A., Thaler, H. T., Sukenick, G. D., Locasale, J. W., Blasberg, R. G., Koutcher, J. A., et al. (2015) · Neoplasia · doi:10.1016/j.neo.2015.08.005 · Cited by 161
“To further investigate the TCA cycle activity and metabolite contributions to anaplerosis [29], we considered a dynamic flux analysis based on the time-course changes of the different (13)C-glutamate isotopomers (Figure 3, A and B).”
MethodLipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity
Patterson, R. E., Kalavalapalli, S., Williams, C. M., Nautiyal, M., Mathew, J. T., Martinez, J., Reinhard, M. K., McDougall, D. J., Rocca, J. R., Yost, R. A., et al. (2016) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00492.2015 · Cited by 161
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
