citric acid cycle


Summary: A series of oxidative reactions in the breakdown of acetyl units derived from GLUCOSE; FATTY ACIDS; or AMINO ACIDS by means of tricarboxylic acid intermediates. The end products are CARBON DIOXIDE, water, and energy in the form of phosphate bonds.

Top Publications

  1. Butch C, Cope E, Pollet P, Gelbaum L, Krishnamurthy R, Liotta C. Production of tartrates by cyanide-mediated dimerization of glyoxylate: a potential abiotic pathway to the citric acid cycle. J Am Chem Soc. 2013;135:13440-5 pubmed publisher
    ..decarboxylation to form pyruvate are known processes that provide a ready feedstock for entry into the citric acid cycle. While glyoxylate and high hydroxide concentration are atypical in the prebiotic literature, there is ..
  2. Priddy C, Kajimoto M, Ledee D, Bouchard B, Isern N, Olson A, et al. Myocardial oxidative metabolism and protein synthesis during mechanical circulatory support by extracorporeal membrane oxygenation. Am J Physiol Heart Circ Physiol. 2013;304:H406-14 pubmed publisher
  3. Olson A, Ledee D, Iwamoto K, Kajimoto M, O Kelly Priddy C, Isern N, et al. C-Myc induced compensated cardiac hypertrophy increases free fatty acid utilization for the citric acid cycle. J Mol Cell Cardiol. 2013;55:156-64 pubmed publisher
    ..hearts and (13)Carbon ((13)C)-NMR were used to measure function and fractional contributions (Fc) to the citric acid cycle by using perfusate containing (13)C-labeled free fatty acids, acetoacetate, lactate, unlabeled glucose and ..
  4. Yuan Y, Kadiyala C, Ching T, Hakimi P, Saha S, Xu H, et al. Enhanced energy metabolism contributes to the extended life span of calorie-restricted Caenorhabditis elegans. J Biol Chem. 2012;287:31414-26 pubmed publisher
    ..We conclude that an increase, not a decrease in fuel consumption, via an accelerated oxidation of fuels in the TCA cycle is involved in life span regulation; this mechanism may be conserved across phylogeny. ..
  5. Steinhauser D, Fernie A, Araujo W. Unusual cyanobacterial TCA cycles: not broken just different. Trends Plant Sci. 2012;17:503-9 pubmed publisher
  6. Macrae J, Sheiner L, Nahid A, Tonkin C, Striepen B, McConville M. Mitochondrial metabolism of glucose and glutamine is required for intracellular growth of Toxoplasma gondii. Cell Host Microbe. 2012;12:682-92 pubmed publisher
    ..Thus, T. gondii tachyzoites have metabolic flexibility that likely allows the parasite to infect diverse cell types...
  7. Sweetlove L, Beard K, Nunes Nesi A, Fernie A, Ratcliffe R. Not just a circle: flux modes in the plant TCA cycle. Trends Plant Sci. 2010;15:462-70 pubmed publisher
    ..Thus, alternative, non-cyclic flux modes occur in leaves in the light, in some developing oilseeds, and under specific physiological circumstances such as anoxia. ..
  8. Feng X, Mouttaki H, Lin L, Huang R, Wu B, Hemme C, et al. Characterization of the central metabolic pathways in Thermoanaerobacter sp. strain X514 via isotopomer-assisted metabolite analysis. Appl Environ Microbiol. 2009;75:5001-8 pubmed publisher
    ..This study demonstrates the merits of combining (13)C-assisted metabolite analysis, enzyme assays, and metabolite detection not only to examine genome sequence annotations but also to discover novel enzyme activities...
  9. Lücker S, Wagner M, Maixner F, Pelletier E, Koch H, Vacherie B, et al. A Nitrospira metagenome illuminates the physiology and evolution of globally important nitrite-oxidizing bacteria. Proc Natl Acad Sci U S A. 2010;107:13479-84 pubmed publisher

Scientific Experts

More Information


  1. Frezza C, Pollard P, Gottlieb E. Inborn and acquired metabolic defects in cancer. J Mol Med (Berl). 2011;89:213-20 pubmed publisher
  2. Xu Q, Vu H, Liu L, Wang T, Schaefer W. Metabolic profiles show specific mitochondrial toxicities in vitro in myotube cells. J Biomol NMR. 2011;49:207-19 pubmed publisher
    ..The close coupling of the TCA cycle to the electron transfer chain (ETC) in OXPHOS enables specific diagnoses of inhibition to ETC complexes by discrete biochemical changes in the TCA cycle. ..
  3. Alves T, Befroy D, Kibbey R, Kahn M, Codella R, Carvalho R, et al. Regulation of hepatic fat and glucose oxidation in rats with lipid-induced hepatic insulin resistance. Hepatology. 2011;53:1175-81 pubmed publisher
  4. Saunders E, Ng W, Chambers J, Ng M, Naderer T, Krömer J, et al. Isotopomer profiling of Leishmania mexicana promastigotes reveals important roles for succinate fermentation and aspartate uptake in tricarboxylic acid cycle (TCA) anaplerosis, glutamate synthesis, and growth. J Biol Chem. 2011;286:27706-17 pubmed publisher
  5. Araujo W, Tohge T, Ishizaki K, Leaver C, Fernie A. Protein degradation - an alternative respiratory substrate for stressed plants. Trends Plant Sci. 2011;16:489-98 pubmed publisher
  6. Gaglio D, Metallo C, Gameiro P, Hiller K, Danna L, Balestrieri C, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. 2011;7:523 pubmed publisher
    ..These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells. ..
  7. Frezza C, Zheng L, Folger O, Rajagopalan K, MacKenzie E, Jerby L, et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature. 2011;477:225-8 pubmed publisher
  8. Metallo C, Gameiro P, Bell E, Mattaini K, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011;481:380-4 pubmed publisher
    ..These results identify a critical role for oxygen in regulating carbon use to produce AcCoA and support lipid synthesis in mammalian cells. ..
  9. Sunny N, Parks E, Browning J, Burgess S. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab. 2011;14:804-10 pubmed publisher
    ..These data indicate that mitochondrial oxidative metabolism is ~2-fold greater in those with NAFLD, providing a potential link between IHTG content, oxidative stress, and liver damage. ..
  10. Olson A, Bouchard B, Ning X, Isern N, Rosiers C, Portman M. Triiodothyronine increases myocardial function and pyruvate entry into the citric acid cycle after reperfusion in a model of infant cardiopulmonary bypass. Am J Physiol Heart Circ Physiol. 2012;302:H1086-93 pubmed publisher
    ..model of infant cardiopulmonary bypass to test the hypothesis that T3 modulates pyruvate entry into the citric acid cycle (CAC), thereby providing the energy support for improved cardiac function after ischemia-reperfusion (I/R)...
  11. Mitchell C, Savage D, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest. 2010;120:1345-54 pubmed publisher
  12. Chambers J, Maguire T, Alwine J. Glutamine metabolism is essential for human cytomegalovirus infection. J Virol. 2010;84:1867-73 pubmed publisher
  13. Binsl T, Alders D, Heringa J, Groeneveld A, van Beek J. Computational quantification of metabolic fluxes from a single isotope snapshot: application to an animal biopsy. Bioinformatics. 2010;26:653-60 pubmed publisher
    ..A web interface for using the software on our computer grid is available under ..
  14. Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, et al. Regulation of cellular metabolism by protein lysine acetylation. Science. 2010;327:1000-4 pubmed publisher
    ..Our study reveals that acetylation plays a major role in metabolic regulation. ..
  15. Wang J, Jiang J, Jazwinski S. Gene regulatory changes in yeast during life extension by nutrient limitation. Exp Gerontol. 2010;45:621-31 pubmed publisher
    ..These gene regulatory events portend an increase in the generation of biosynthetic intermediates necessary for the production of daughter cells, which is the measure of yeast replicative life span. ..
  16. Zanatta A, Schuck P, Viegas C, Knebel L, Busanello E, Moura A, et al. In vitro evidence that D-serine disturbs the citric acid cycle through inhibition of citrate synthase activity in rat cerebral cortex. Brain Res. 2009;1298:186-93 pubmed publisher
    ..from glucose and acetate, glucose uptake and the activities of the respiratory chain complexes I-IV, of the citric acid cycle enzymes citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate ..
  17. Tcherkez G, Mahé A, Gauthier P, Mauve C, Gout E, Bligny R, et al. In folio respiratory fluxomics revealed by 13C isotopic labeling and H/D isotope effects highlight the noncyclic nature of the tricarboxylic acid "cycle" in illuminated leaves. Plant Physiol. 2009;151:620-30 pubmed publisher
  18. Niklas J, Noor F, Heinzle E. Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2. Toxicol Appl Pharmacol. 2009;240:327-36 pubmed publisher
  19. Kaleta C, de Figueiredo L, Schuster S. Can the whole be less than the sum of its parts? Pathway analysis in genome-scale metabolic networks using elementary flux patterns. Genome Res. 2009;19:1872-83 pubmed publisher
    ..Finally, we give an outlook on further applications like the computation of minimal media, the development of knockout strategies, and the analysis of combined genome-scale networks. ..
  20. Alteri C, Smith S, Mobley H. Fitness of Escherichia coli during urinary tract infection requires gluconeogenesis and the TCA cycle. PLoS Pathog. 2009;5:e1000448 pubmed publisher
  21. Marrero J, Rhee K, Schnappinger D, Pethe K, Ehrt S. Gluconeogenic carbon flow of tricarboxylic acid cycle intermediates is critical for Mycobacterium tuberculosis to establish and maintain infection. Proc Natl Acad Sci U S A. 2010;107:9819-24 pubmed publisher
    ..Mtb thus relies on gluconeogenesis throughout the infection. PEPCK depletion also attenuated Mtb in IFNgamma-deficient mice, suggesting that this enzyme represents an attractive target for chemotherapy. ..
  22. Kaelin W. SDH5 mutations and familial paraganglioma: somewhere Warburg is smiling. Cancer Cell. 2009;16:180-2 pubmed publisher
    ..Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma. ..
  23. Saladino R, Brucato J, De Sio A, Botta G, Pace E, Gambicorti L. Photochemical synthesis of citric acid cycle intermediates based on titanium dioxide. Astrobiology. 2011;11:815-24 pubmed publisher
    The emergence of the citric acid cycle is one of the most remarkable occurrences with regard to understanding the origin and evolution of metabolic pathways...
  24. Dalla Betta P, Schulte M. Calculation of the aqueous thermodynamic properties of citric acid cycle intermediates and precursors and the estimation of high temperature and pressure equation of state parameters. Int J Mol Sci. 2009;10:2809-37 pubmed publisher
    The citric acid cycle (CAC) is the central pathway of energy transfer for many organisms, and understanding the origin of this pathway may provide insight into the origins of metabolism...
  25. Zhang S, Bryant D. The tricarboxylic acid cycle in cyanobacteria. Science. 2011;334:1551-3 pubmed publisher
    ..Closely related genes occur in the genomes of some methanogens and other anaerobic bacteria, which are also thought to have incomplete TCA cycles...
  26. DeBerardinis R, Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29:313-24 pubmed publisher
    ..In this study we review the protean roles of glutamine in cancer, both in the direct support of tumor growth and in mediating some of the complex effects on whole-body metabolism that are characteristic of tumor progression. ..
  27. Wise D, Ward P, Shay J, Cross J, Gruber J, Sachdeva U, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of ?-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011;108:19611-6 pubmed publisher
    ..These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions. ..
  28. Baughn A, Garforth S, Vilcheze C, Jacobs W. An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acid cycle of Mycobacterium tuberculosis. PLoS Pathog. 2009;5:e1000662 pubmed publisher
    ..As these pathways are regulated by metabolic cues, we predict that their differential utilization provides an advantage for growth in different environments within the host. ..
  29. Sulpice R, Sienkiewicz Porzucek A, Osorio S, Krahnert I, Stitt M, Fernie A, et al. Mild reductions in cytosolic NADP-dependent isocitrate dehydrogenase activity result in lower amino acid contents and pigmentation without impacting growth. Amino Acids. 2010;39:1055-66 pubmed publisher
    ..These data are discussed within the context of current models for the role of the various isoforms of isocitrate dehydrogenase within plant amino acid metabolism. ..
  30. Tahara E, Cezário K, Souza Pinto N, Barros M, Kowaltowski A. Respiratory and TCA cycle activities affect S. cerevisiae lifespan, response to caloric restriction and mtDNA stability. J Bioenerg Biomembr. 2011;43:483-91 pubmed publisher
    ..Altogether, our data indicate that respiratory integrity is required for lifespan extension by CR and that mtDNA stability is regulated by nucleoid proteins in a glucose-sensitive manner. ..
  31. Amador Noguez D, Feng X, Fan J, Roquet N, Rabitz H, Rabinowitz J. Systems-level metabolic flux profiling elucidates a complete, bifurcated tricarboxylic acid cycle in Clostridium acetobutylicum. J Bacteriol. 2010;192:4452-61 pubmed publisher
  32. Bayley J, Devilee P. Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree?. Curr Opin Genet Dev. 2010;20:324-9 pubmed publisher
    ..Here we discuss these diverse hypotheses and highlight very recent findings on the possible effects of IDH gene mutations...
  33. Tang K, Feng X, Zhuang W, Alvarez Cohen L, Blankenship R, Tang Y. Carbon flow of heliobacteria is related more to clostridia than to the green sulfur bacteria. J Biol Chem. 2010;285:35104-12 pubmed publisher
    ..Moreover, in contrast to (Si)-citrate synthase, (Re)-citrate synthase produces a different isomer of 2-fluorocitrate that is not expected to inhibit the activity of aconitase...
  34. Bowden S, Ramachandran V, Knudsen G, Hinton J, Thompson A. An incomplete TCA cycle increases survival of Salmonella Typhimurium during infection of resting and activated murine macrophages. PLoS ONE. 2010;5:e13871 pubmed publisher
  35. Kadir T, Mannan A, Kierzek A, McFadden J, Shimizu K. Modeling and simulation of the main metabolism in Escherichia coli and its several single-gene knockout mutants with experimental verification. Microb Cell Fact. 2010;9:88 pubmed publisher
    ..The comparison of the simulation result with the experimental data indicates that the present model could simulate the effect of the specific gene knockouts to the changes in the metabolisms to some extent. ..
  36. Fendt S, Oliveira A, Christen S, Picotti P, Dechant R, Sauer U. Unraveling condition-dependent networks of transcription factors that control metabolic pathway activity in yeast. Mol Syst Biol. 2010;6:432 pubmed publisher
  37. Bulusu V, Jayaraman V, Balaram H. Metabolic fate of fumarate, a side product of the purine salvage pathway in the intraerythrocytic stages of Plasmodium falciparum. J Biol Chem. 2011;286:9236-45 pubmed publisher
    ..This study, therefore, provides a biosynthetic function for fumarate hydratase, malate quinone oxidoreductase, and aspartate aminotransferase of P. falciparum. ..
  38. Summermatter S, Troxler H, Santos G, Handschin C. Coordinated balancing of muscle oxidative metabolism through PGC-1? increases metabolic flexibility and preserves insulin sensitivity. Biochem Biophys Res Commun. 2011;408:180-5 pubmed publisher
    ..Thus, in mice fed a normal chow diet, over-expression of PGC-1? does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1? mimic the beneficial effects of endurance training on muscle metabolism in this context. ..
  39. Massilamany C, Gangaplara A, Gardner D, Musser J, Steffen D, Somerville G, et al. TCA cycle inactivation in Staphylococcus aureus alters nitric oxide production in RAW 264.7 cells. Mol Cell Biochem. 2011;355:75-82 pubmed publisher
    ..This may also explain the occurrence of TCA cycle mutants in clinical S. aureus isolates. ..
  40. Kriegeskorte A, König S, Sander G, Pirkl A, Mahabir E, Proctor R, et al. Small colony variants of Staphylococcus aureus reveal distinct protein profiles. Proteomics. 2011;11:2476-90 pubmed publisher
    ..In conclusion, physiological changes between normal and SCV S. aureus phenotypes are more complex than reflected by defined electron transport chain-interrupting mutants and their complemented counterparts. ..
  41. Sadykov M, Mattes T, Luong T, Zhu Y, Day S, Sifri C, et al. Tricarboxylic acid cycle-dependent synthesis of Staphylococcus aureus Type 5 and 8 capsular polysaccharides. J Bacteriol. 2010;192:1459-62 pubmed publisher
    ..Consistent with this hypothesis, S. aureus tricarboxylic acid cycle mutants fail to make capsule. ..
  42. Chen A, Hurd R, Schroeder M, Lau A, Gu Y, Lam W, et al. Simultaneous investigation of cardiac pyruvate dehydrogenase flux, Krebs cycle metabolism and pH, using hyperpolarized [1,2-(13)C2]pyruvate in vivo. NMR Biomed. 2012;25:305-11 pubmed publisher
  43. Sienkiewicz Porzucek A, Sulpice R, Osorio S, Krahnert I, Leisse A, Urbanczyk Wochniak E, et al. Mild reductions in mitochondrial NAD-dependent isocitrate dehydrogenase activity result in altered nitrate assimilation and pigmentation but do not impact growth. Mol Plant. 2010;3:156-73 pubmed publisher
  44. Bricker D, Taylor E, Schell J, Orsak T, Boutron A, Chen Y, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science. 2012;337:96-100 pubmed publisher
    ..These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier. ..
  45. Gao X, Cui J, Zheng X, Li Z, Choi Y, Zhou Y, et al. An investigation of the antidepressant action of xiaoyaosan in rats using ultra performance liquid chromatography-mass spectrometry combined with metabonomics. Phytother Res. 2013;27:1074-85 pubmed publisher
    ..Metabonomic methods are valuable tools for measuring efficacy and mechanisms of action in the study of traditional Chinese medicines. ..
  46. Li C, Wang E, Wang J. Landscape topography determines global stability and robustness of a metabolic network. ACS Synth Biol. 2012;1:229-39 pubmed publisher
    ..We found there is a strong correlation between the landscape topography and the input-output response. The more stable and robust the metabolic network is, the sharper the response is. ..
  47. Bolisetty S, Traylor A, Zarjou A, Johnson M, Benavides G, Ricart K, et al. Mitochondria-targeted heme oxygenase-1 decreases oxidative stress in renal epithelial cells. Am J Physiol Renal Physiol. 2013;305:F255-64 pubmed publisher
  48. Grassian A, Parker S, Davidson S, Divakaruni A, Green C, Zhang X, et al. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res. 2014;74:3317-31 pubmed publisher
    ..Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. ..
  49. Theodosiou E, Breisch M, Julsing M, Falcioni F, Bühler B, Schmid A. An artificial TCA cycle selects for efficient ?-ketoglutarate dependent hydroxylase catalysis in engineered Escherichia coli. Biotechnol Bioeng. 2017;114:1511-1520 pubmed publisher
    ..Biotechnol. Bioeng. 2017;114: 1511-1520. © 2017 Wiley Periodicals, Inc...
  50. Calderón Santiago M, Priego Capote F, Galache Osuna J, Luque de Castro M. Method based on GC-MS to study the influence of tricarboxylic acid cycle metabolites on cardiovascular risk factors. J Pharm Biomed Anal. 2013;74:178-85 pubmed publisher
    ..These interactions were crucial to explain the levels of target TCA metabolites. Statistical evaluation by ROC curves allowed discrimination of the capability of significant metabolites with the occurrence of coronary lesions. ..
  51. Adijanto J, Du J, Moffat C, Seifert E, Hurle J, Philp N. The retinal pigment epithelium utilizes fatty acids for ketogenesis. J Biol Chem. 2014;289:20570-82 pubmed
    ..Collectively, our data support a novel mechanism of RPE-retina metabolic coupling in which RPE cells metabolize fatty acids to produce ?-HB, which is transported to the retina for use as a metabolic substrate. ..
  52. Wang Y, Wang H, Xu J, Tan J, Fu L, Wang J, et al. Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner. Nat Commun. 2018;9:545 pubmed publisher
    ..Clinically, overexpression of SIRT5 is significantly correlated with poor prognosis in CRC. Thus, SIRT5 supports the anaplerotic entry of glutamine into the TCA cycle in malignant phenotypes of CRC via activating GLUD1. ..