This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: TCA cycle -- aerobic respiration, tricarboxylic acid cycle, citric acid cycle, Szent-Gyorgyi-Krebs cycle, Krebs cycle
|Superclasses:||Generation of Precursor Metabolites and Energy → TCA cycle|
The TCA pathway is a catabolic pathway of aerobic respiration that generates both energy and reducing power. In addition, it is also the first step in generating precursors for biosynthesis. The pathway is very common, and a variation of it exists in practically all aerobic living organisms [Krebs37, Krebs38, Krebs45].
The input to the cycle is acetyl-CoA, an activated form of acetate that is generated by the degradation of carbohydrates, fats and proteins. A common source of acetyl-coA is pyruvate, which is generated by glycolysis and converted to acetyl-CoA by the pyruvate dehydrogenase complex.
In every turn the TCA cycle converts one molecule of acetyl-CoA into two CO2 molecules, reduces a total of four molecules of either NAD+, NADP+, or quinone to NADH, NADPH and quinol, respectively, and phosphorylates one molecule of GDP to GTP.
The reduced molecules of NADH/NADPH/quinol that are formed by the TCA cycle serve as electron donors for oxidative phosphorylation (see for example aerobic respiration I (cytochrome c)). In that process the electrons flow to a terminal acceptor, powering on their way proton pumps that transport protons across the cytoplasmic or mitochondrial membranes, generating a proton motive force (PMF). As the protons return to their original location, they power ATPase enzymes that phosphorylate ADP molecules to ATP. The total energy gained from the complete breakdown of one molecule of glucose by glycolysis, the TCA cycle, and oxidative phosphorylation equals about 30 ATP molecules in eukaryotes.
The name of the TCA (short for tricarboxylic acid) cycle is derived from the fact that the first step in the pathway is attachment of acetyl-coA to citrate, an acid with three carboxylate groups. The pathway is also known as the citric acid cycle, and as the Szent-Gyorgyi-Krebs cycle (or just the Krebs cycle), named after the scientists who described it.
About This Pathway
One of the main differences between the eukaryotic TCA cycles (described in this pathway and in TCA cycle III (animals)) and the prokaryotic pathway is that the latter contains an alternative route between (S)-malate and oxaloacetate, catalyzed by EC 126.96.36.199, malate dehydrogenase (quinone). That enzyme is found in some bacteria, but is absent from most eukaryotes, in which the reaction is catalyzed only by the NAD+-dependent malate dehydrogenase, EC 188.8.131.52.
Another difference concerns the enzyme isocitrate dehydrogenase. Most prokaryotes possess only an NADP+-dependent form (EC 184.108.40.206, isocitrate dehydrogenase (NADP+)), which supports both respiration via the TCA cycle and glutamate biosynthesis for anabolic reactions. Eukaryotes, on the other hand, have two types of the enzyme - an NADP+-dependent forms (EC 220.127.116.11) and NAD+-dependent forms (EC 18.104.22.168). It has been shown that the NADP+-dependent enzymes are involved primarily in glutamate biosynthesis, while the NAD+-dependent enzymes are those involved in the TCA cycle [Keys90]. It should be noted that while rare, NAD+-dependent isocitrate dehydrogenases are also found in bacteria that lack the glyoxylate bypass, and thus are missing the enzyme isocitrate lyase [Zhu05a]. Examples for prokaryotes that contain an NAD-dependent enzyme include Acidithiobacillus thiooxidans [Inoue02] and Zymomonas mobilis [Wang12b].
The only difference between this pathway, found in plants and fungi, and TCA cycle III (animals), which is found in animals, is the step between succinyl-CoA and succinate. While plants and fungi only use EC 22.214.171.124, succinate—CoA ligase (ADP-forming), animals also use EC 126.96.36.199, succinate—CoA ligase (GDP-forming).
Variants: superpathway of glyoxylate bypass and TCA , TCA cycle I (prokaryotic) , TCA cycle III (animals) , TCA cycle IV (2-oxoglutarate decarboxylase) , TCA cycle V (2-oxoglutarate:ferredoxin oxidoreductase) , TCA cycle VI (obligate autotrophs) , TCA cycle VII (acetate-producers) , TCA cycle VIII (helicobacter)
Inoue02: Inoue H, Tamura T, Ehara N, Nishito A, Nakayama Y, Maekawa M, Imada K, Tanaka H, Inagaki K (2002). "Biochemical and molecular characterization of the NAD(+)-dependent isocitrate dehydrogenase from the chemolithotroph Acidithiobacillus thiooxidans." FEMS Microbiol Lett 214(1);127-32. PMID: 12204383
Keys90: Keys DA, McAlister-Henn L (1990). "Subunit structure, expression, and function of NAD(H)-specific isocitrate dehydrogenase in Saccharomyces cerevisiae." J Bacteriol 172(8);4280-7. PMID: 2198251
Nimmo87: Nimmo HG, Borthwick AC, el-Mansi EM, Holms WH, MacKintosh C, Nimmo GA (1987). "Regulation of the enzymes at the branchpoint between the citric acid cycle and the glyoxylate bypass in Escherichia coli." Biochem Soc Symp 1987;54;93-101. PMID: 3333001
Walsh84: Walsh K, Koshland DE (1984). "Determination of flux through the branch point of two metabolic cycles. The tricarboxylic acid cycle and the glyoxylate shunt." J Biol Chem 1984;259(15);9646-54. PMID: 6378912
Wang12b: Wang P, Jin M, Zhu G (2012). "Biochemical and molecular characterization of NAD(+)-dependent isocitrate dehydrogenase from the ethanologenic bacterium Zymomonas mobilis." FEMS Microbiol Lett 327(2);134-41. PMID: 22117777
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
Anderson88: Anderson DH, Duckworth HW (1988). "In vitro mutagenesis of Escherichia coli citrate synthase to clarify the locations of ligand binding sites." J Biol Chem 1988;263(5);2163-9. PMID: 3276685
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
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.
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
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
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
Buttlaire77: Buttlaire DH, Chon M (1977). "Interactions of phospho- and dephosphosuccinyl coenzyme A synthetase with manganous ion and substrates. Studies of manganese complexes by NMR relaxation rates of water protons." J Biol Chem 252(6);1957-64. PMID: 321448
Collier78: Collier GE, Nishimura JS (1978). "Affinity labeling of succinyl-CoA synthetase from porcine heart and Escherichia coli with oxidized coenzyme A disulfide." J Biol Chem 253(14);4938-43. PMID: 353044
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