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MetaCyc Pathway: reductive TCA cycle I

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Synonyms: reductive tricarboxylic acid cycle, reductive tricarboxylic acid pathway, reductive citric acid cycle, reverse citric acid cycle, carbon fixation, CO2 fixation, reductive carboxylic acid cycle

Superclasses: Degradation/Utilization/Assimilation C1 Compounds Utilization and Assimilation CO2 Fixation Autotrophic CO2 Fixation Reductive TCA Cycles

Some taxa known to possess this pathway include ? : Aquifex pyrophilus , Candidatus Arcobacter sulfidicus , Chlorobaculum tepidum , Chlorobaculum thiosulfatiphilum , Chlorobium limicola , Desulfobacter hydrogenophilus , Pyrobaculum islandicum , Pyrobaculum neutrophilum , Sulfurimonas denitrificans , Thermoproteus tenax

Expected Taxonomic Range: Aquificae , Archaea , Bacteroidetes/Chlorobi group , Chlamydomonas , Proteobacteria

General Background

The reductive tricarboxylic acid (TCA) cycle is a carbon dioxide fixation pathway found in autotrophic eubacteria and archaea (there is a report of the pathway also operating in a strain of the green algae Chlamydomonas reinhardtii [Chen92]). It is considered to be a primordial pathway for production of starting organic molecules for biosynthesis of sugars, lipids, amino acids, pyrimidines and pyrroles [Smith04a, Romano96, Buchanan90].

Other pathways for carbon dioxide fixation include the Calvin-Benson-Bassham cycle, the reductive acetyl coenzyme A pathway, and the 3-hydroxypropanoate cycle.

The reductive TCA cycle is largely the oxidative, catabolic TCA cycle in reverse. Most of the enzymes of the TCA cycle work reversibly and could catalyze both directions. Only three counteracting enzyme pairs are thought to determine the oxidative or reductive direction of the cycle. These three enzymes are ATP-citrate lyase; 2-oxoglutarate synthase; and fumarate reductase (the names provided here are the names of the enzyme catalyzing the reductive direction) [Schauder87, Shiba85, Siebers04]. It should be noted that these enzymes may participate in other pathways (for example, 2-oxoglutarate synthase also participates in the oxidative TCA cycle found in Helicobacteraceae). Nonetheless, the presence of these enzyme activities in autotrophically grown bacteria and archaea is considered indicative of the presence of the reductive TCA cycle.

Activities of the key enzymes in the reductive TCA cycle have been demonstrated in the following autotrophic bacteria and archaea: the green sulfur bacterium Chlorobium limicola [Kanao01, Fuchs80]; the δ proteobacterium Desulfobacter hydrogenophilus [Schauder87]; the α proteobacterium strain MC-1 [Williams06]; the ε proteobacteria Sulfurimonas denitrificans and Candidatus Arcobacter sulfidicus [Hugler05]; seven other ε proteobacteria isolated from deep-sea hydrothermal environments [Takai05]; the aquificales Hydrogenobacter thermophilus and Aquifex pyrophilus [Beh93, Shiba85]; and the Crenarchaeota Pyrobaculum neutrophilum [Schafer89, Beh93] and Pyrobaculum islandicum [Hugler03].

In additon, the genes of the reductive TCA cycle have been demonstrated in Chlorobaculum tepidum TLS [Eisen02], and Thermoproteus tenax [Siebers04].

In a few cases, the presence of both the oxidative and reductive TCA cycles has been shown in the same organism, as in Thermoproteus tenax and Pyrobaculum islandicum [Selig94, Siebers04, Hugler03].

About This Pathway

The pathway described here was first discovered in the green sulfur bacterium Chlorobaculum thiosulfatiphilum [Evans66]. The key step of converting citrate to oxaloacetate and acetyl-coA is catalyzed by the enzyme ATP-citrate lyase.

The basic cycle results in the fixation of two molecules of carbon dioxide and the production of one molecule of acetyl-CoA [Hugler05, Takai05, Siebers04]. Another molecule of carbon dioxide can be fixed by the carboxylation of acetyl-coA to pyruvate [Kanao01]. Pyruvate can be converted to phosphoenolpyruvate, which can enter gluconeogenesis I [Beh93], or, as shown here, can alternatively assimilate a fourth carbon dioxide molecule by carboxylation to oxaloacetate. This carboxylation is catalyzed by phosphoenolpyruvate carboxylase [Kanao01, Romano96, Buchanan90, Schauder87, Evans66].

Variants: incomplete reductive TCA cycle , reductive TCA cycle II

Created 17-Oct-2000 by Pellegrini-Toole A , Marine Biological Laboratory


Beh93: Beh M, Strauss G, Huber R, Stetter K-O, Fuchs G (1993). "Enzymes of the reductive citric acid cycle in the autotrophic eubacterium Aquifex pyrophilus and in the archaebacterium Thermoproteus neutrophilus." Arch Microbiol 160: 306-311.

Buchanan90: Buchanan BB, Arnon DI (1990). "A reverse KREBS cycle in photosynthesis: consensus at last." Photosynth Res 24;47-53. PMID: 11540925

Chen92: Chen C, Gibbs M (1992). "Some Enzymes and Properties of the Reductive Carboxylic Acid Cycle Are Present in the Green Alga Chlamydomonas reinhardtii F-60." Plant Physiol 98(2);535-539. PMID: 16668673

Eisen02: Eisen JA, Nelson KE, Paulsen IT, Heidelberg JF, Wu M, Dodson RJ, Deboy R, Gwinn ML, Nelson WC, Haft DH, Hickey EK, Peterson JD, Durkin AS, Kolonay JL, Yang F, Holt I, Umayam LA, Mason T, Brenner M, Shea TP, Parksey D, Nierman WC, Feldblyum TV, Hansen CL, Craven MB, Radune D, Vamathevan J, Khouri H, White O, Gruber TM, Ketchum KA, Venter JC, Tettelin H, Bryant DA, Fraser CM (2002). "The complete genome sequence of Chlorobium tepidum TLS, a photosynthetic, anaerobic, green-sulfur bacterium." Proc Natl Acad Sci U S A 99(14);9509-14. PMID: 12093901

Evans66: Evans MC, Buchanan BB, Arnon DI (1966). "A new ferredoxin-dependent carbon reduction cycle in a photosynthetic bacterium." Proc Natl Acad Sci U S A 55(4);928-34. PMID: 5219700

Fuchs80: Fuchs G, Stupperich E, Eden G (1980). "Autotrophic CO2 fixation in Chlorobium limicola. Evidence for the operation of a reductive tricarboxylic acid cycle in growing cells." Arch Microbiol 128: 64-71.

Hugler03: Hugler M, Huber H, Stetter KO, Fuchs G (2003). "Autotrophic CO2 fixation pathways in archaea (Crenarchaeota)." Arch Microbiol 179(3);160-73. PMID: 12610721

Hugler05: Hugler M, Wirsen CO, Fuchs G, Taylor CD, Sievert SM (2005). "Evidence for autotrophic CO2 fixation via the reductive tricarboxylic acid cycle by members of the epsilon subdivision of proteobacteria." J Bacteriol 187(9);3020-7. PMID: 15838028

Kanao01: Kanao T, Fukui T, Atomi H, Imanaka T (2001). "ATP-citrate lyase from the green sulfur bacterium Chlorobium limicola is a heteromeric enzyme composed of two distinct gene products." Eur J Biochem 268(6);1670-8. PMID: 11248686

Romano96: Romano AH, Conway T (1996). "Evolution of carbohydrate metabolic pathways." Res Microbiol 147(6-7);448-55. PMID: 9084754

Schafer89: Schafer S, Gotz M, Eisenreich W, Bacher A, Fuchs G (1989). "13C-NMR study of autotrophic CO2 fixation in Thermoproteus neutrophilus." Eur J Biochem 184(1);151-6. PMID: 2506014

Schauder87: Schauder R, Widdel F, Fuchs G (1987). "Carbon assimilation pathways in sulfate-reducing bacteria II. Enzymes of a reductive citric acid cycle in the autotrophic Desulfobacter hydrogenophilus." Arch Microbiol 148: 218-225.

Selig94: Selig M, Schonheit P (1994). "Oxidation of organic compounds to CO2 with sulfur or thiosulfate as electron acceptor in the anaerobic hyperthermophilic archaea Thermoproteus tenax and Pyrobaculum islandicum proceeds via the citric acid cycle." Arch Microbiol 162: 286-294.

Shiba85: Shiba H, Kawasumi T, Igarashi Y, Kodama T, Minoda Y (1985). "The CO2 assimilation via the reductive tricarboxylic acid cycle in an obligately autotrophic, aerobic hydrogen-oxidizing bacterium, Hydrogenobacter thermophilus." Arch Microbiol 141: 198-203.

Siebers04: Siebers B, Tjaden B, Michalke K, Dorr C, Ahmed H, Zaparty M, Gordon P, Sensen CW, Zibat A, Klenk HP, Schuster SC, Hensel R (2004). "Reconstruction of the central carbohydrate metabolism of Thermoproteus tenax by use of genomic and biochemical data." J Bacteriol 186(7);2179-94. PMID: 15028704

Smith04a: Smith E, Morowitz HJ (2004). "Universality in intermediary metabolism." Proc Natl Acad Sci U S A 101(36);13168-73. PMID: 15340153

Takai05: Takai K, Campbell BJ, Cary SC, Suzuki M, Oida H, Nunoura T, Hirayama H, Nakagawa S, Suzuki Y, Inagaki F, Horikoshi K (2005). "Enzymatic and genetic characterization of carbon and energy metabolisms by deep-sea hydrothermal chemolithoautotrophic isolates of Epsilonproteobacteria." Appl Environ Microbiol 71(11);7310-20. PMID: 16269773

Williams06: Williams TJ, Zhang CL, Scott JH, Bazylinski DA (2006). "Evidence for autotrophy via the reverse tricarboxylic acid cycle in the marine magnetotactic coccus strain MC-1." Appl Environ Microbiol 72(2);1322-9. PMID: 16461683

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Allen64: Allen, S.H., Kellermeyer, R.W., Ssjernholm, R.L., Wood, H.G. (1964). "Purification and properties of enzymes involved in the propionic acid fermentation." J Bacteriol 87;171-87. PMID: 14102852

Aoshima04: Aoshima M, Ishii M, Igarashi Y (2004). "A novel enzyme, citryl-CoA lyase, catalysing the second step of the citrate cleavage reaction in Hydrogenobacter thermophilus TK-6." Mol Microbiol 52(3);763-70. PMID: 15101982

Aoshima04a: Aoshima M, Ishii M, Igarashi Y (2004). "A novel enzyme, citryl-CoA synthetase, catalysing the first step of the citrate cleavage reaction in Hydrogenobacter thermophilus TK-6." Mol Microbiol 52(3);751-61. PMID: 15101981

Bailey99: Bailey DL, Fraser ME, Bridger WA, James MN, Wolodko WT (1999). "A dimeric form of Escherichia coli succinyl-CoA synthetase produced by site-directed mutagenesis." J Mol Biol 285(4);1655-66. PMID: 9917403

Banerjee05: Banerjee S, Nandyala A, Podili R, Katoch VM, Hasnain SE (2005). "Comparison of Mycobacterium tuberculosis isocitrate dehydrogenases (ICD-1 and ICD-2) reveals differences in coenzyme affinity, oligomeric state, pH tolerance and phylogenetic affiliation." BMC Biochem 6;20. PMID: 16194279

Baughn09: Baughn AD, Garforth SJ, Vilcheze C, Jacobs WR (2009). "An anaerobic-type alpha-ketoglutarate ferredoxin oxidoreductase completes the oxidative tricarboxylic acid cycle of Mycobacterium tuberculosis." PLoS Pathog 5(11);e1000662. PMID: 19936047

Bennett95: Bennett B, Gruer MJ, Guest JR, Thomson AJ (1995). "Spectroscopic characterisation of an aconitase (AcnA) of Escherichia coli." Eur J Biochem 233(1);317-26. PMID: 7588761

Berkemeyer98: Berkemeyer M, Scheibe R, Ocheretina O (1998). "A novel, non-redox-regulated NAD-dependent malate dehydrogenase from chloroplasts of Arabidopsis thaliana L." J Biol Chem 273(43);27927-33. PMID: 9774405

Berman67: Berman K, Itada N, Cohn M (1967). "On the mechanism of ATP cleavage in the phosphoenolpyruvate synthase reaction of Escherichia coli." Biochim Biophys Acta 141(1);214-6. PMID: 4860971

Berman70: Berman KM, Cohn M (1970). "Phosphoenolpyruvate synthetase of Escherichia coli. Purification, some properties, and the role of divalent metal ions." J Biol Chem 245(20);5309-18. PMID: 4319237

Berman70a: Berman KM, Cohn M (1970). "Phosphoenolpyruvate synthetase. Partial reactions studied with adenosine triphosphate analogues and the inorganic phosphate-H2 18O exchange reaction." J Biol Chem 245(20);5319-25. PMID: 4319238

Bernstein78: Bernstein LH, Grisham MB, Cole KD, Everse J (1978). "Substrate inhibition of the mitochondrial and cytoplasmic malate dehydrogenases." J Biol Chem 253(24);8697-701. PMID: 214429

Bild80: Bild GS, Janson CA, Boyer PD (1980). "Subunit interaction during catalysis. ATP modulation of catalytic steps in the succinyl-CoA synthetase reaction." J Biol Chem 255(17);8109-15. PMID: 6997289

Birney96: Birney M, Um HD, Klein C (1996). "Novel mechanisms of Escherichia coli succinyl-coenzyme A synthetase regulation." J Bacteriol 178(10);2883-9. PMID: 8631677

Birney97: Birney M, Um H, Klein C (1997). "Multiple levels of regulation of Escherichia coli succinyl-CoA synthetase." Arch Biochem Biophys 347(1);103-12. PMID: 9344470

Blamey93: Blamey JM, Adams MW (1993). "Purification and characterization of pyruvate ferredoxin oxidoreductase from the hyperthermophilic archaeon Pyrococcus furiosus." Biochim Biophys Acta 1161(1);19-27. PMID: 8380721

Blamey94: Blamey JM, Adams MW (1994). "Characterization of an ancestral type of pyruvate ferredoxin oxidoreductase from the hyperthermophilic bacterium, Thermotoga maritima." Biochemistry 1994;33(4);1000-7. PMID: 8305426

Blaschkowski82: Blaschkowski HP, Neuer G, Ludwig-Festl M, Knappe J (1982). "Routes of flavodoxin and ferredoxin reduction in Escherichia coli. CoA-acylating pyruvate: flavodoxin and NADPH: flavodoxin oxidoreductases participating in the activation of pyruvate formate-lyase." Eur J Biochem 123(3);563-9. PMID: 7042345

BochudAllemann02: Bochud-Allemann N, Schneider A (2002). "Mitochondrial substrate level phosphorylation is essential for growth of procyclic Trypanosoma brucei." J Biol Chem 277(36);32849-54. PMID: 12095995

Bonnarme95: Bonnarme P, Gillet B, Sepulchre AM, Role C, Beloeil JC, Ducrocq C (1995). "Itaconate biosynthesis in Aspergillus terreus." J Bacteriol 177(12);3573-8. PMID: 7768868

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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