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 can function as a major anaplerotic source of OAA through the activity of mitochondrial pyruvate carboxylase (PC).
“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]
Cataplerosis of any TCA cycle intermediate requires compensatory input to sustain TCA cycle activity, a process termed anaplerosis.
“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]
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, the maintenance of a robust pathway for the folding and secretion of high abundance circulating proteins such as adiponectin, and interactions between mitochondrial function and components of the insulin-sign
“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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“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
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“as a source of precursors for macromolecular synthesis in addition to generating reducing equivalents for oxidative phosphorylation [81].”
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“The details of the pathway of cataplerosis have been reviewed previously (39, 40).”
MethodGlucose metabolism and cardiac hypertrophy
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“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
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Inflammasomes on the Crossroads of Innate Immune Recognition and Metabolic Control
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The functional roles of TCA cycle metabolites in cancer
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“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
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“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 268 · see citing works
“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 269 · see citing works
“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 253 · see citing works
Ferroptosis and its emerging roles in cardiovascular diseases
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Metabolic Remodeling Promotes Cardiac Hypertrophy by Directing Glucose to Aspartate Biosynthesis
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Glutamine Metabolism in Cancer
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“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
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Carboxylases in Natural and Synthetic Microbial Pathways
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Regulation of Tumor Progression by Programmed Necrosis
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Serine Catabolism Feeds NADH when Respiration Is Impaired
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“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 · see citing works
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“…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
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“This leads to a situation where more ATP is used and cataplerosis provides a constant out fl ow of intermediates [14,15].”
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“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
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“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
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Wnt/Snail Signaling Regulates Cytochrome c Oxidase and Glucose Metabolism
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“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).”
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Metabolism in Pulmonary Hypertension
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Ins and outs of the TCA cycle: the central role of anaplerosis
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The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis
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“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
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“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.”
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“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
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“Substrate level phosphorylation such as glycolysis also contributes a limited amount of ATP to the cellular energy pool [3].”
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Metabolic reprogramming and metabolic dependency in T cells
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“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
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“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
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“This decrease in pdk4 could potentially promote glyceroneogenic formation of G3P (8) via cataplerosis (45).”
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“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).”
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“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
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“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 · see citing works
- 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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