If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Locations of Mapped Genes:
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Reductants Biosynthesis|
Thiols play major roles in the cell in maintaining redox balance, a reduced environment, and defense against reactive oxygen species. In most organisms the major thiol is the tripeptide glutathione (>-γ-glutamyl-L-cysteinylglycine, GSH). Most of the glutathione pool is kept in its reduced form. In E. coli, the ratio of reduced to oxidized glutathione is approximately 200:1 [Ritz01a]. The functionality of glutathione largely depends on its being in a reduced form.
In E. coli two pathways utilize NADPH to reduce disulfide bonds, the thioredoxin system (see thioredoxin pathway) and the glutaredoxin system (described here). Glutaredoxins are ubiquitous oxidoreductase enzymes that perform some essential cytoplasmic redox reactions using glutathione as an electron donor. For example they can serve as a hydrogen donor for the glutathione-dependent reduction of enzymes such as ribonucleoside diphosphate reductase 1, 3'-phospho-adenylylsulfate reductase and arsenate reductase. Four glutaredoxins have been identified in E. coli, Grx1, Grx2, Grx3 and Grx4 which have both overlapping and distinct activities [Shi99a, Ritz01a, Ortenberg03, Fernandes05, Elgan10] (see oxidized glutaredoxin 1, reduced glutaredoxin 1, oxidized glutaredoxin 2, reduced glutaredoxin 2, oxidized glutaredoxin 3, reduced glutaredoxin 3, and glutaredoxin 4).
About This Pathway
After reducing protein disulfide groups back to their native form, the resulting oxidized glutaredoxins (shown here as a class an oxidized glutaredoxin) are reduced back to their active form ( a reduced glutaredoxin) with electrons donated by reduced glutathione molecules. In this reaction two molecules of the reduced form of glutathione are oxidized, condensing them into the single molecule glutathione disulfide. This may be a nonenzymatic process. No experimental evidence for an E. coli enzyme that specifically catalyzes the reduction of Grx1, Grx2 or Grx3 was found in a literature search, although a protein disulfide oxidoreductase could hypothetically catalyze this reaction. The glutathione disulfide is then reduced back into two individual glutathione molecules by the action of the NADPH utilizing enzyme glutathione reductase encoded by gene gor.
CarmelHarel00: Carmel-Harel O, Storz G (2000). "Roles of the glutathione- and thioredoxin-dependent reduction systems in the Escherichia coli and saccharomyces cerevisiae responses to oxidative stress." Annu Rev Microbiol 54;439-61. PMID: 11018134
Elgan10: Elgan TH, Planson AG, Beckwith J, Guntert P, Berndt KD (2010). "Determinants of activity in glutaredoxins: an in vitro evolved Grx1-like variant of Escherichia coli Grx3." Biochem J 430(3);487-95. PMID: 20604742
Fernandes04: Fernandes AP, Holmgren A (2004). "Glutaredoxins: glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system." Antioxid Redox Signal 6(1);63-74. PMID: 14713336
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
Shi99a: Shi J, Vlamis-Gardikas A, Aslund F, Holmgren A, Rosen BP (1999). "Reactivity of glutaredoxins 1, 2, and 3 from Escherichia coli shows that glutaredoxin 2 is the primary hydrogen donor to ArsC-catalyzed arsenate reduction." J Biol Chem 1999;274(51);36039-42. PMID: 10593884
Arscott89: Arscott LD, Drake DM, Williams CH (1989). "Inactivation-reactivation of two-electron reduced Escherichia coli glutathione reductase involving a dimer-monomer equilibrium." Biochemistry 28(8);3591-8. PMID: 2663073
Davis82: Davis NK, Greer S, Jones-Mortimer MC, Perham RN (1982). "Isolation and mapping of glutathione reductase-negative mutants of Escherichia coli K12." J Gen Microbiol 128(7);1631-4. PMID: 6214613
Deonarain89: Deonarain MP, Berry A, Scrutton NS, Perham RN (1989). "Alternative proton donors/acceptors in the catalytic mechanism of the glutathione reductase of Escherichia coli: the role of histidine-439 and tyrosine-99." Biochemistry 28(25);9602-7. PMID: 2558727
Deonarain90: Deonarain MP, Scrutton NS, Berry A, Perham RN (1990). "Directed mutagenesis of the redox-active disulphide bridge in glutathione reductase from Escherichia coli." Proc R Soc Lond B Biol Sci 1990;241(1302);179-86. PMID: 1979442
Deonarain92: Deonarain MP, Scrutton NS, Perham RN (1992). "Engineering surface charge. 2. A method for purifying heterodimers of Escherichia coli glutathione reductase." Biochemistry 31(5);1498-504. PMID: 1737009
Deonarain92a: Deonarain MP, Scrutton NS, Perham RN (1992). "Engineering surface charge. 1. A method for detecting subunit exchange in Escherichia coli glutathione reductase." Biochemistry 31(5);1491-7. PMID: 1737008
Greer86: Greer S, Perham RN (1986). "Glutathione reductase from Escherichia coli: cloning and sequence analysis of the gene and relationship to other flavoprotein disulfide oxidoreductases." Biochemistry 25(9);2736-42. PMID: 3521741
Henderson91: Henderson GB, Murgolo NJ, Kuriyan J, Osapay K, Kominos D, Berry A, Scrutton NS, Hinchliffe NW, Perham RN, Cerami A (1991). "Engineering the substrate specificity of glutathione reductase toward that of trypanothione reduction." Proc Natl Acad Sci U S A 88(19);8769-73. PMID: 1924337
Kunert90: Kunert KJ, Cresswell CF, Schmidt A, Mullineaux PM, Foyer CH (1990). "Variations in the activity of glutathione reductase and the cellular glutathione content in relation to sensitivity to methylviologen in Escherichia coli." Arch Biochem Biophys 1990;282(2);233-8. PMID: 2241146
Lasserre06: Lasserre JP, Beyne E, Pyndiah S, Lapaillerie D, Claverol S, Bonneu M (2006). "A complexomic study of Escherichia coli using two-dimensional blue native/SDS polyacrylamide gel electrophoresis." Electrophoresis 27(16);3306-21. PMID: 16858726
Lillig03: Lillig CH, Potamitou A, Schwenn JD, Vlamis-Gardikas A, Holmgren A (2003). "Redox regulation of 3'-phosphoadenylylsulfate reductase from Escherichia coli by glutathione and glutaredoxins." J Biol Chem 278(25);22325-30. PMID: 12682041
Mata84: Mata AM, Pinto MC, Lopez-Barea J (1984). "Purification by affinity chromatography of glutathione reductase (EC 184.108.40.206) from Escherichia coli and characterization of such enzyme." Z Naturforsch [C] 39(9-10);908-15. PMID: 6393625
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