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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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“Glucogenic amino acid carbon skeletons can also enter the CAC by being metabolized into intermediates such as α-ketoglutarate, succinyl CoA, fumarate or oxaloacetate [105] which is especially important for anaplerotic maintenance of CAC intermediate levels during gluconeogenesis and lipogenesis [112].”
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Expression of Pyruvate Carboxylase in Cultured Oligodendroglial, Microglial and Ependymal Cells
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“The enzymatic formation of oxaloacetate, a member of the tricarboxylic acid (TCA) cycle, serves an important anaplerotic function by replenishing the TCA cycle [3].”
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“Other intermediates, including isocitrate, malate, and aspartate, are indispensable for the generation of nicotinamide adenine dinucleotide phosphate (NADPH) to counteract oxidative stress in cancer cells 7 .”
Mitochondrial Dysfunction and Metabolic Disturbances Induced by Viral Infections
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Mass isotopomer study of anaplerosis from propionate in the perfused rat heart
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PCB126 Inhibits the Activation of AMPK-CREB Signal Transduction Required for Energy Sensing in Liver
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“Functionally, the enzymes “translated” from these genes are either anaplerotic or cataplerotic in generating the reaction products that are precursor metabolites during glucose production (Owen et al., 2002).”
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Citric Acid Cycle Regulation: Back Bone for Secondary Metabolite Production
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“Although this process may contribute to glucose production (18), the primary role of renal PEPCK is interpreted as removal of Krebs cycle intermediates (the process called “cataplerosis”) to guarantee the accelerated catabolism of glutamine and glutamate to generate ammonia for H+ buffering (10, 17, 41).”
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“As one of the basic amino acids of nitrogen metabolism in body, glutamate has great significance on the metabolism, which is not only the intermediate metabolite of the tricarboxylic acid cycle [4], but also the element source of purine base and pyrimidine.”
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“For example pyrurate carboxylases which can provide key intermediates-glycerol for the synthesis of triglycerides only exist in mitochondrial [ 22 ]; the MRC function is required for fat accumulation [10].”
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“Glucose is an important fuel for exercising muscles; the scarcity of carbohydrate reserves in liver reduces pyruvate levels that are a substrate for both acetyl-coenzyme A formation and inception of anaplerotic reaction for continuous oxidation of free fatty acids or amino acids [47].”
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“in TCA intermediates through anaplerosis (Figure 3E) (18).”
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“We surmise from these observations that the ACN1generated acetyl-CoA pool is a substrate for the glyoxylate cycle, labeling succinate, citrate, malate, and fumarate, and these organic acids can serve as substrates for amination or transamination reactions that generate amino acids such as Asp, Glu, Gln, GABA, Pro, and…”
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Mitochondrial donation in translational medicine; from imagination to reality
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“For the metabolism of proteins, glutamine is further catabolized to produce glutamate, which is by itself transformed into α-ketoglutarate [21].”
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Pheochromocytoma: Gasping for Air
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Pseudomonas aeruginosa MifS-MifR Two-Component System Is Specific for α-Ketoglutarate Utilization
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“The TCA cycle is an amphibolic pathway that serves two main purposes: energy-generation in aerobic organisms (catabolism), and the generation of intermediates to serve as biosynthetic precursors for fatty acid, amino acid and carbohydrate synthesis (anabolism) [22].”
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“The analysis of downregulated transcripts showed that in addition to those involved in carbohydrate metabolism and TCA cycle above discussed, other genes related to glycolysis (i.e. triose-phosphate isomerase, TIM, #29) and GO:0006139 nucleobase, nucleoside, nucleotide and nucleic acid metabolic process 6 2.99 % GO:00…”
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“Well studied in photosynthesis, anaplerosis incorporates CO2 via a b-carboxylase into C4 intermediates, using ATP [72–76].”
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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