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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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“Activated GOGAT promotes glutamate accumulation and subsequently removes 2-oxoglutarate which results in cataplerosis of the TCA cycle and nett glutamate accumulation (Fig 1) [9].”
Baker, P. R., Patinkin, Z. W., Shapiro, A. L. B., de la Houssaye, B. A., Woontner, M., Boyle, K. E., Vanderlinden, L. A., Dabelea, D., & Friedman, J. E. (2017) · JCI Insight · doi:10.1172/jci.insight.94200 · Cited by 46
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Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts
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“The conversion of glutamine to glutamate by glutaminase (GLS) [14] and subsequent conversion to the TCA cycle intermediate α-ketoglutarate (α-KG) by glutamate dehydrogenase (GLUD1) is an important mechanism through which the TCA cycle can utilise amino acids to assist with driving mitochondrial energy production [15].”
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“Since pyruvate carboxylase plays a important role in replenishment of TCA cycle intermediates (by the conversion of pyruvate to oxaloacetate) to facilitate fatty acid synthesis (28,29), the suppressed PEPCK and unchanged pyruvate carboxylase gene expressions in the refed fld mice would favor the redirection of metabol…”
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“The two processes of cataplerosis and anaplerosis assist in transporting intermediates of the TCA cycle in and out of the mitochondria to stabilize the cycle [102].”
BackgroundMultiplexed Quantification for Data-Independent Acquisition
Minogue, C. E., Hebert, A. S., Rensvold, J. W., Westphall, M. S., Pagliarini, D. J., & Coon, J. J. (2015) · Analytical Chemistry · doi:10.1021/ac503593d · Cited by 45
Ko, C., Counihan, D. R., Wu, J., Hatzoglou, M., Puchowicz, M. A., & Croniger, C. M. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.819136 · Cited by 45
“Recently, in tumor cells that exhibit the Warburg effect, Pck1 was discovered to play a key role for promoting anabolic metabolism, including synthesis of fatty acids and nucleic acids (13).”
BackgroundShi, W. M., Han, Y., Guan, X., Rong, J., Du, X., Zha, S., Tang, Y., & Liu, G. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00377 · Cited by 45
Gu, J., Huang, C., Hu, X., Xia, J., Shao, W., & Lin, D. (2020) · Cancer Science · doi:10.1111/cas.14443 · Cited by 45
Geda, F., Rekecki, A., Decostere, A., Bossier, P., Wuyts, B., Kalmar, I. D., & Janssens, G. P. J. (2012) · Animal Feed Science and Technology · doi:10.1016/j.anifeedsci.2012.09.008 · Cited by 44
Soares, R. A. N., Vargas, G., Muniz, M. M. M., Soares, M. A. M., Cánovas, Á., Schenkel, F. S., & Squires, E. J. (2020) · Journal of Dairy Science · doi:10.3168/jds.2020-18883 · Cited by 43
Flees, J. J., Ganguly, B., & Dridi, S. (2020) · Poultry Science · doi:10.1016/j.psj.2020.12.060 · Cited by 48
“ment of the TCA cycle) via converting malate into pyruvate, which re-enters the mitochondria via the pyruvate transporter resulting in increased ATP synthesis (Owen et al., 2002).”
Beta-cell mitochondrial carriers and the diabetogenic stress response
Brun, T., & Maechler, P. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.03.012 · Cited by 46
“leak out of TCA cycle intermediates [76].”
A ketogenic diet normalizes interictal cortical but not subcortical responsivity in migraineurs
Lorenzo, C. D., Coppola, G., Bracaglia, M., Lenola, D. D., Sirianni, G., Rossi, P. D., Lorenzo, G. D., Parisi, V., Serrao, M., Cervenka, M. C., et al. (2019) · BMC Neurology · doi:10.1186/s12883-019-1351-1 · Cited by 43
Sinton, M. C., Hay, D. C., & Drake, A. J. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0702-5 · Cited by 44
PCK1 Regulates Glycolysis and Tumor Progression in Clear Cell Renal Cell Carcinoma Through LDHA
Shi, L., An, S., Liu, Y., Liu, J., & Wang, F. (2020) · OncoTargets and Therapy · doi:10.2147/ott.s241717 · Cited by 45
“In addition to its primary function in gluconeogenesis, the conversion of OAA to PEP catalyzed by PCK1 maintains metabolic flux through the tricarboxylic acid (TCA) cycle by removing excess oxaloacetate (cataplerosis) and replenishing required TCA intermediates (anaplerosis).(10) Because of its role in endogenous gluc…”
BackgroundA clinically attainable dose of L‐asparaginase targets glutamine addiction in lymphoid cell lines
Sugimoto, K., Suzuki, H. I., Fujimura, T., Ono, A., Kaga, N., Isobe, Y., Sasaki, M., Taka, H., Miyazono, K., & Komatsu, N. (2015) · Cancer Science · doi:10.1111/cas.12807 · Cited by 42
Wang, L., Hou, E., Wang, Z., Sun, N., He, L., Chen, L., Liang, M., & Tian, Z. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.06.089 · Cited by 42
“Furthermore, molecules involved in biosynthetic pathways, in which intermediates leave TCA cycle to be converted primarily to glucose, fatty acids or non-essential amino acids [24], were also different between the two groups.”
BackgroundYin, F., Yin, Y., Zhang, Z., Xie, M., Huang, J., Huang, R., & Li, T. (2011) · British Journal Of Nutrition · doi:10.1017/s0007114511000213 · Cited by 42
A disease-associated Aifm1 variant induces severe myopathy in knockin mice
Wischhof, L., Gioran, A., Sonntag‐Bensch, D., Piazzesi, A., Stork, M., Nicotera, P., & Bano, D. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.05.002 · Cited by 39
“Since mitochondrial lesions alter serine and folate-driven 1C metabolism, we assessed the expression levels of enzymes that contribute to compensatory cataplerotic reactions [53,54].”
BackgroundRole of coenzymes in cancer metabolism
Thapa, M., & Dallmann, G. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.027 · Cited by 45
Tricarboxylic acid cycle enzyme activities in a mouse model of methylmalonic aciduria
Wongkittichote, P., Cunningham, G. R., Summar, M. L., Pumbo, E., Forny, P., Baumgartner, M. R., & Chapman, K. A. (2019) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2019.10.007 · Cited by 42
“On the other hand, impaired anaplerosis of the TCA cycle might be due to the decreased production of succinyl-CoA by MMUT in the propionate pathway, as well as by formation of 2-methylcitrate, which reduces availability of oxaloacetate [20,21].”
BackgroundVarshavi, D., Varshavi, D., McCarthy, N., Veselkov, K., Keun, H. C., & Everett, J. R. (2020) · Metabolomics · doi:10.1007/s11306-020-01674-2 · Cited by 41
Human Papillomavirus-related Cancers and Mitochondria
Cruz‐Gregorio, A., Aranda‐Rivera, A. K., & Pedraza‐Chaverrí, J. (2020) · Virus Research · doi:10.1016/j.virusres.2020.198016 · Cited by 45
DNA Damage Response Protein CHK2 Regulates Metabolism in Liver Cancer
Lulli, M., Coco, L. D., Mello, T., Sukowati, C. H. C., Madiai, S., Gragnani, L., Forte, P., Fanizzi, F. P., Mazzocca, A., Rombouts, K., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3134 · Cited by 41
“, aspartate, glutamate, alanine) that effectively removes intermediates from the cycle (36).”
BackgroundVenturini, G., Malagrino, P. A., Padilha, K., Tanaka, L. Y., Laurindo, F. R. M., Dariolli, R., Carvalho, V. M., Cardozo, K. H. M., Krieger, J. E., & Pereira, A. C. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00128.2018 · Cited by 39
Gorgoglione, R., Impedovo, V., Riley, C. L., Fratantonio, D., Tiziani, S., Palmieri, L., Dolce, V., & Fiermonte, G. (2022) · Cancers · doi:10.3390/cancers14010245 · Cited by 44
“Mitochondrial glutamine catabolism produces 4- and 5-carbon (C4 and C5) intermediates in the matrix that KC cannot fully oxidize, and these intermediates must be removed from the cycle via cataplerosis, otherwise some KC reactions would be inhibited [99].”
BackgroundMetabolism of Preimplantation Embryo Development
Kaneko, K. J. (2016) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2016.04.010 · Cited by 48
THOMAS, M. P., Davis, T., Loos, B., Sishi, B., Huisamen, B., Strijdom, H., & Engelbrecht, A. (2018) · Cell Biochemistry and Function · doi:10.1002/cbf.3318 · Cited by 45
Li, B., Zhang, B., Wang, P., Cai, X., Chen, Y., Yang, Y., Liu, Z., & Zheng, Y. (2022) · ACS Synthetic Biology · doi:10.1021/acssynbio.2c00055 · Cited by 42
Azzazy, H. M. E.-S., Mansour, M. M. H., & Christenson, R. H. (2009) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2009.01.001 · Cited by 41
“PEPCK is a prime cataplerotic enzyme, but potentially has an anaplerotic action as well since it can also catalyze the reverse reaction; OAA synthesis from PEP [17,21].”
BackgroundMetabolic programming a lean phenotype by deregulation of RNA polymerase III
Willis, I. M., Moir, R. D., & Hernandez, N. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815590115 · Cited by 40
“2) and allowing entry of the carbon skeletons into the TCA cycle for further oxidation by the electron transport chain (28).”
BackgroundBiophysical and physiological processes causing oxygen loss from coral reefs
Silveira, C. B., Luque, A., Roach, T. N. F., Villela, H., Barno, A. R., Green, K., Reyes, B., Rubio‐Portillo, E., Le, T., Mead, S., et al. (2019) · eLife · doi:10.7554/elife.49114 · Cited by 39
Kumar, A., Welch, N., Mishra, S., Bellar, A., Silva, R. N., Li, L., Singh, S. S., Sharkoff, M., Kerr, A., Chelluboyina, A. K., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.154089 · Cited by 40
“Anaplerotic substrates in the skeletal muscle include branched chain amino acids and glucose (5).”
BackgroundDai, W., White, R. R., Liu, J., & Liu, H. (2022) · Progress in Lipid Research · doi:10.1016/j.plipres.2022.101159 · Cited by 42
Metabolic fate of fructose in human adipocytes: a targeted 13C tracer fate association study
Varma, V., Boros, L. G., Nolen, G. T., Chang, C., Wabitsch, M., Beger, R. D., & Kaput, J. (2014) · Metabolomics · doi:10.1007/s11306-014-0716-0 · Cited by 41
“Pyruvate enters into the TCA cycle under aerobic conditions to generate ATP via substrate-level and oxidative phosphorylation.”
BackgroundEngström, W., Darbre, P. D., Eriksson, S., Gulliver, L., Hultman, T., Karamouzis, M. V., Klaunig, J. E., Mehta, R., Moorwood, K., Sanderson, J. T., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv030 · Cited by 40
Li, X., Wang, Z., Zhang, G., & Yi, L. (2018) · Chemical Engineering Science · doi:10.1016/j.ces.2018.09.030 · Cited by 39
Sulfur-Oxidizing Symbionts without Canonical Genes for Autotrophic CO 2 Fixation
Seah, B. K. B., Antony, C. P., Hüettel, B., Zarzycki, J., von Borzyskowski, L. S., Erb, T. J., Kouris, A., Kleiner, M., Liebeke, M., Dubilier, N., et al. (2019) · mBio · doi:10.1128/mbio.01112-19 · Cited by 39
“, via anaplerotic reactions in the oxidative TCA cycle (43).”
Lee, J. D., Kim, H. Y., Kang, K., Jeong, H. G., Song, M., Tae, I. H., Lee, S. H., Kim, H.-R., Lee, K., Chae, S., et al. (2020) · Archives of Toxicology · doi:10.1007/s00204-020-02657-x · Cited by 40
Pendleton, A. L., Antolic, A. T., Kelly, A. C., Davis, M. A., Camacho, L. E., Doubleday, K., Anderson, M. J., Langlais, P. R., Lynch, R. M., & Limesand, S. W. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00057.2020 · Cited by 39
Intraoral Microbial Metabolism and Association with Host Taste Perception
Gardner, A., So, P., & Carpenter, G. H. (2020) · Journal of Dental Research · doi:10.1177/0022034520917142 · Cited by 39
“Pyruvate can be converted into both alanine and acetoin (March et al. 2002; Owen et al. 2002), as well entering the citric acid cycle or being converted to lactate.”
Pant, A., Dsouza, L., Cao, S., Peng, C., & Yang, Z. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009303 · Cited by 39
“Citrate is essential not only to drive the TCA cycle forward in the mitochondria but is also transported to the cytosol to be used for fatty acid biosynthesis [16].”
BackgroundZhang, Y., Li, R., Chen, W., Li, Y., & Chen, G. (2011) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-011-0831-4 · Cited by 39
Jing, J. L., Cheng, T. Y. N., Natali, F., Eisenhaber, F., & Alfatah, M. (2022) · Cells · doi:10.3390/cells11050862 · Cited by 36
“These findings supported the anti-aging activity of iron supplementation, as regular export of TCA cycle intermediates affects the mitochondrial integrity [47].”
BackgroundDu, L., Wang, H., Xu, W., Zeng, Y., Hou, Y., Zhang, Y.-Q., Zhao, X.-J., & Sun, C.-H. (2013) · Toxicological Sciences · doi:10.1093/toxsci/kft091 · Cited by 37
“The result indicated that exposure to a mixture of OP pesticides affected the tricarboxylic acid (TCA) cycle and the lipid metabolism of rat (Attia and Nasr, 2009; KEGG; Li et al., 2010; Ohta et al., 2009; Owen et al., 2002; Yu et al., 2011).”
BackgroundImmunological Aspects of Chytridiomycosis
Grogan, L. F., Humphries, J. E., Robert, J., Lanctôt, C. M., Nock, C. J., Newell, D., & McCallum, H. I. (2020) · Journal of Fungi · doi:10.3390/jof6040234 · Cited by 38
Singh, S. S., Kumar, A., Welch, N., Sekar, J., Mishra, S., Bellar, A., Gangadhariah, M. H., Attaway, A. H., Alkhafaji, H. A. A.-R., Wu, X., et al. (2021) · Cellular Physiology and Biochemistry · doi:10.33594/000000327 · Cited by 38
Song, J.-E., Alves, T. C., Stutz, B., Šestan-Peša, M., Kilian, N., Jin, S., Diano, S., Kibbey, R. G., & Horváth, T. L. (2021) · Metabolites · doi:10.3390/metabo11050322 · Cited by 37
“These experiments were performed at a metabolic steady state (4-h incubation), so the amount of cataplerosis must be balanced by an equivalent amount of anaplerosis (the entrance of metabolites into the TCA cycle) [21,31].”
MethodGLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity
Bierling, T. E. H., Gumann, A., Ottmann, S. R., Schulz, S. R., Weckwerth, L., Thomas, J., Gessner, A., Wichert, M., Kuwert, F., Rost, F., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113739 · Cited by 38
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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