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.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Reductants Biosynthesis|
The thiol redox system of Escherichia coli consists of the thioredoxin pathway (shown here) and the glutathione/glutaredoxin pathway (see glutathione redox reactions II). Electrons from NADPH flow through these pathways via gradients in redox potentials. Thioredoxin and glutaredoxin reduce disulfide bonds by a thiol-disulfide exchange mechanism involving two active site cysteine residues in the motif CXXC (where X is any amino acid) that form either a disulfide or a dithiol. In addition to the importance of thiol redox potential [Mossner99], other important factors in the thiol redox system are cellular location [Debarbieux98] and the overall redox state of the cell. Both the thioredoxin and glutathione pathways appear to operate in parallel. Genetic studies in Escherichia coli have shown the two pathways to be functionally redundant during aerobic growth, although inactivation of both pathways results in unviability. Reviewed in [Toledano07, VlamisGardikas08, Ritz01a].
The thioredoxin pathway is involved in reducing important cytoplasmic enzymes such as the essential ribonucleotide reductase, as well as 3'-phosphoadenosine-5'-phosphosulfate reductase and methionine sulfoxide reductases A and B. Escherichia coli thioredoxin also binds to bacteriophage T7 DNA polymerase and serves as its processivity factor for polymerization during phage growth ([Etson10] and in [Doublie98]). In addition, many other proteins that may interact with thioredoxin have been identified [Leichert04, Kumar04a]. Thioredoxin is also involved in a pathway for the trans-membrane transfer of reducing potential from the cytoplasm to the periplasm to reduce the protein disulfide isomerase DbsC [Rietsch97, Cho09]. After acting as a reductant, disulfide-containing oxidized thioredoxin is reduced back to a dithiol by thioredoxin reductase, an FAD-containing, NADPH-dependent enzyme. Reviewed in [Toledano07].
The thiol redox system is present in taxonomic groups from archaea to man. However, despite structural and mechanistic similariteis between prokaryotic and eukaryotic thiol redox systems, their overall cellular functions differ (reviewed in [Toledano07] and [Arner00]).
About This Pathway
In this pathway diagram, clicking on the protein class named "a reduced thioredoxin" will display a page showing two instances of this class named reduced thioredoxin 2 and reduced thioredoxin 1. These proteins are the products of Escherichia coli genes trxC and trxA, respectively. Clicking on either of the instance names will display a page showing some structural and functional properties of the respective protein.
Again in the pathway diagram, clicking on the protein class named "an oxidized thioredoxin" will display a page showing two instances of this class named oxidized thioredoxin 1 and oxidized thioredoxin 2. Note that in the gene-reaction schematic shown on this page the reduced thioredoxins are considered to be the direct gene products and their oxidized forms are shown separately as modified forms of the gene products.
In Escherichia coli TrxA is a more well studied thiol-disulfide oxidoreductase than TrxC (Trx2). TrxC was identified later as a novel thioredoxin that forms a subfamily of the TrxA protein family. The gene encoding TrxC is under control of the transcriptional regulator OxyR which responds to oxidative stress, although the biological role of TrxC remains to be fully elucidated [MirandaVizuete97, Collet03].
Unification Links: EcoCyc:THIOREDOX-PWY
Collet03: Collet JF, D'Souza JC, Jakob U, Bardwell JC (2003). "Thioredoxin 2, an oxidative stress-induced protein, contains a high affinity zinc binding site." J Biol Chem 278(46);45325-32. PMID: 12952960
Debarbieux98: Debarbieux L, Beckwith J (1998). "The reductive enzyme thioredoxin 1 acts as an oxidant when it is exported to the Escherichia coli periplasm." Proc Natl Acad Sci U S A 95(18);10751-6. PMID: 9724776
Doublie98: Doublie S, Tabor S, Long AM, Richardson CC, Ellenberger T (1998). "Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 A resolution." Nature 391(6664);251-8. PMID: 9440688
Etson10: Etson CM, Hamdan SM, Richardson CC, van Oijen AM (2010). "Thioredoxin suppresses microscopic hopping of T7 DNA polymerase on duplex DNA." Proc Natl Acad Sci U S A 107(5);1900-5. PMID: 20080681
MirandaVizuete97: Miranda-Vizuete A, Damdimopoulos AE, Gustafsson J, Spyrou G (1997). "Cloning, expression, and characterization of a novel Escherichia coli thioredoxin." J Biol Chem 272(49);30841-7. PMID: 9388228
Mossner99: Mossner E, Huber-Wunderlich M, Rietsch A, Beckwith J, Glockshuber R, Aslund F (1999). "Importance of redox potential for the in vivo function of the cytoplasmic disulfide reductant thioredoxin from Escherichia coli." J Biol Chem 274(36);25254-9. PMID: 10464247
Rietsch97: Rietsch A, Bessette P, Georgiou G, Beckwith J (1997). "Reduction of the periplasmic disulfide bond isomerase, DsbC, occurs by passage of electrons from cytoplasmic thioredoxin." J Bacteriol 179(21);6602-8. PMID: 9352906
Toledano07: Toledano MB, Kumar C, Le Moan N, Spector D, Tacnet F (2007). "The system biology of thiol redox system in Escherichia coli and yeast: differential functions in oxidative stress, iron metabolism and DNA synthesis." FEBS Lett 581(19);3598-607. PMID: 17659286
VlamisGardikas08: Vlamis-Gardikas A (2008). "The multiple functions of the thiol-based electron flow pathways of Escherichia coli: Eternal concepts revisited." Biochim Biophys Acta 1780(11);1170-200. PMID: 18423382
Al12: Al Mamun AA, Lombardo MJ, Shee C, Lisewski AM, Gonzalez C, Lin D, Nehring RB, Saint-Ruf C, Gibson JL, Frisch RL, Lichtarge O, Hastings PJ, Rosenberg SM (2012). "Identity and function of a large gene network underlying mutagenic repair of DNA breaks." Science 338(6112);1344-8. PMID: 23224554
Arner99: Arner ES, Sarioglu H, Lottspeich F, Holmgren A, Bock A (1999). "High-level expression in Escherichia coli of selenocysteine-containing rat thioredoxin reductase utilizing gene fusions with engineered bacterial-type SECIS elements and co-expression with the selA, selB and selC genes." J Mol Biol 292(5);1003-16. PMID: 10512699
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
Ding05: Ding H, Harrison K, Lu J (2005). "Thioredoxin reductase system mediates iron binding in IscA and iron delivery for the iron-sulfur cluster assembly in IscU." J Biol Chem 280(34);30432-7. PMID: 15985427
Dyson90: Dyson HJ, Gippert GP, Case DA, Holmgren A, Wright PE (1990). "Three-dimensional solution structure of the reduced form of Escherichia coli thioredoxin determined by nuclear magnetic resonance spectroscopy." Biochemistry 1990;29(17);4129-36. PMID: 2193685
Eklund84: Eklund H, Cambillau C, Sjoberg BM, Holmgren A, Jornvall H, Hoog JO, Branden CI (1984). "Conformational and functional similarities between glutaredoxin and thioredoxins." EMBO J 1984;3(7);1443-9. PMID: 6378624
Fernandes05: Fernandes AP, Fladvad M, Berndt C, Andresen C, Lillig CH, Neubauer P, Sunnerhagen M, Holmgren A, Vlamis-Gardikas A (2005). "A novel monothiol glutaredoxin (Grx4) from Escherichia coli can serve as a substrate for thioredoxin reductase." J Biol Chem 280(26);24544-52. PMID: 15833738
Fujiwara99: Fujiwara N, Fujii T, Fujii J, Taniguchi N (1999). "Functional expression of rat thioredoxin reductase: selenocysteine insertion sequence element is essential for the active enzyme." Biochem J 340 ( Pt 2);439-44. PMID: 10333487
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