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MetaCyc Pathway: glutathionylspermidine biosynthesis
Inferred from experiment

Enzyme View:

Pathway diagram: glutathionylspermidine biosynthesis

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: BiosynthesisAmines and Polyamines Biosynthesis
BiosynthesisCofactors, Prosthetic Groups, Electron Carriers BiosynthesisReductants Biosynthesis

Some taxa known to possess this pathway include : Crithidia fasciculata, Escherichia coli B, Escherichia coli K-12 substr. MG1655

Expected Taxonomic Range: Bacteria , Eukaryota

Polyamines (such as spermidine) and thiols (such as glutathione) are found in millimolar concentrations in most living organisms. Polyamines have a variety of roles, including charge neutralization and complexation of the anionic phosphodiester backbone of DNA. Thiols also have many roles, including detoxification of xenobiotics and reactive oxygen species, maintaining the redox balance in the cell, and serving as cofactors for many enzymatic reactions (see γ-glutamyl cycle).

Several organisms are able to conjugate the two together, by forming an amide link between spermidine and glutathione, resulting in either of the two forms N1-glutathionylspermidine, or N8-glutathionylspermidine.

This compound was first discovered in Escherichia coli [Dubin59], but was not characterized in regard to its physiological role. Later it was shown that the compound is present in the pathogenetic protozoa Trypanosoma and Leishmania [Fairlamb85]. In these parasites, a second glutathione molecule is added to glutathionylspermidine, forming trypanothione, which in these organisms provides the functional roles of glutathione (see trypanothione biosynthesis).

The conjugation of glutathione and spermidine to glutathionylspermidine can be catalyzed by either of two enzymes. In Escherichia coli the only enzyme that can catalyze the reaction is glutathionylspermidine synthetase. However, it has been shown that in Trypanosomes both glutathionylspermidine synthetase and trypanothione synthetase can catalyze the reaction. The second enzyme also catalyzes the conversion of glutathionylspermidine to trypanothione.

Glutathionylspermidine can be recycled back to spermidine and glutathione by an amidase activity ( glutathionylspermidine + H2O ↔ glutathione + spermidine) which both of these enzymes possess [Kwon97].

Another amide derivative of glutathione is glutathione amide (see glutathione amide metabolism).

Unification Links: EcoCyc:PWY-4121

Created 02-Aug-2005 by Caspi R, SRI International


Dubin59: Dubin, D. T. (1959). "Evidence for conjugates between polyamines and glutathione in E. coli." Biochem. Biophys. Res. Comm. 1(5):262-265.

Fairlamb85: Fairlamb AH, Blackburn P, Ulrich P, Chait BT, Cerami A (1985). "Trypanothione: a novel bis(glutathionyl)spermidine cofactor for glutathione reductase in trypanosomatids." Science 227(4693);1485-7. PMID: 3883489

Kwon97: Kwon DS, Lin CH, Chen S, Coward JK, Walsh CT, Bollinger JM (1997). "Dissection of glutathionylspermidine synthetase/amidase from Escherichia coli into autonomously folding and functional synthetase and amidase domains." J Biol Chem 272(4);2429-36. PMID: 8999955

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

Bollinger95: Bollinger JM, Kwon DS, Huisman GW, Kolter R, Walsh CT (1995). "Glutathionylspermidine metabolism in Escherichia coli. Purification, cloning, overproduction, and characterization of a bifunctional glutathionylspermidine synthetase/amidase." J Biol Chem 1995;270(23);14031-41. PMID: 7775463

Butland05: Butland G, Peregrin-Alvarez JM, Li J, Yang W, Yang X, Canadien V, Starostine A, Richards D, Beattie B, Krogan N, Davey M, Parkinson J, Greenblatt J, Emili A (2005). "Interaction network containing conserved and essential protein complexes in Escherichia coli." Nature 433(7025);531-7. PMID: 15690043

Chen97: Chen S, Lin CH, Kwon DS, Walsh CT, Coward JK (1997). "Design, synthesis, and biochemical evaluation of phosphonate and phosphonamidate analogs of glutathionylspermidine as inhibitors of glutathionylspermidine synthetase/amidase from Escherichia coli." J Med Chem 40(23);3842-50. PMID: 9371250

Chiang10: Chiang BY, Chen TC, Pai CH, Chou CC, Chen HH, Ko TP, Hsu WH, Chang CY, Wu WF, Wang AH, Lin CH (2010). "Protein S-thiolation by Glutathionylspermidine (Gsp): the role of Escherichia coli Gsp synthetASE/amidase in redox regulation." J Biol Chem 285(33);25345-53. PMID: 20530482

Chong11: Chong CM, Gao S, Chiang BY, Hsu WH, Lin TC, Chen TC, Lin CH (2011). "An acyloxymethyl ketone-based probe to monitor the activity of glutathionylspermidine amidase in Escherichia coli." Chembiochem 12(15);2306-9. PMID: 21887840

Comini05: Comini M, Menge U, Wissing J, Flohe L (2005). "Trypanothione synthesis in crithidia revisited." J Biol Chem 280(8);6850-60. PMID: 15537651

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

GOA01a: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

Ishihama08: Ishihama Y, Schmidt T, Rappsilber J, Mann M, Hartl FU, Kerner MJ, Frishman D (2008). "Protein abundance profiling of the Escherichia coli cytosol." BMC Genomics 9;102. PMID: 18304323

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lin97: Lin CH, Kwon DS, Bollinger JM, Walsh CT (1997). "Evidence for a glutathionyl-enzyme intermediate in the amidase activity of the bifunctional glutathionylspermidine synthetase/amidase from Escherichia coli." Biochemistry 36(48);14930-8. PMID: 9398217

Lin97a: Lin CH, Chen S, Kwon DS, Coward JK, Walsh CT (1997). "Aldehyde and phosphinate analogs of glutathione and glutathionylspermidine: potent, selective binding inhibitors of the E. coli bifunctional glutathionylspermidine synthetase/amidase." Chem Biol 4(11);859-66. PMID: 9384533

Oza02: Oza SL, Ariyanayagam MR, Fairlamb AH (2002). "Characterization of recombinant glutathionylspermidine synthetase/amidase from Crithidia fasciculata." Biochem J 364(Pt 3);679-86. PMID: 12049631

Oza02a: Oza SL, Tetaud E, Ariyanayagam MR, Warnon SS, Fairlamb AH (2002). "A single enzyme catalyses formation of Trypanothione from glutathione and spermidine in Trypanosoma cruzi." J Biol Chem 277(39);35853-61. PMID: 12121990

Pai06: Pai CH, Chiang BY, Ko TP, Chou CC, Chong CM, Yen FJ, Chen S, Coward JK, Wang AH, Lin CH (2006). "Dual binding sites for translocation catalysis by Escherichia coli glutathionylspermidine synthetase." EMBO J 25(24);5970-82. PMID: 17124497

Pai11: Pai CH, Wu HJ, Lin CH, Wang AH (2011). "Structure and mechanism of Escherichia coli glutathionylspermidine amidase belonging to the family of cysteine; histidine-dependent amidohydrolases/peptidases." Protein Sci 20(3);557-66. PMID: 21226054

Rajagopala14: Rajagopala SV, Sikorski P, Kumar A, Mosca R, Vlasblom J, Arnold R, Franca-Koh J, Pakala SB, Phanse S, Ceol A, Hauser R, Siszler G, Wuchty S, Emili A, Babu M, Aloy P, Pieper R, Uetz P (2014). "The binary protein-protein interaction landscape of Escherichia coli." Nat Biotechnol 32(3);285-90. PMID: 24561554

Smith95: Smith K, Borges A, Ariyanayagam MR, Fairlamb AH (1995). "Glutathionylspermidine metabolism in Escherichia coli." Biochem J 1995;312 ( Pt 2);465-9. PMID: 8526857

Tetaud98: Tetaud E, Manai F, Barrett MP, Nadeau K, Walsh CT, Fairlamb AH (1998). "Cloning and characterization of the two enzymes responsible for trypanothione biosynthesis in Crithidia fasciculata." J Biol Chem 1998;273(31);19383-90. PMID: 9677355

UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

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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
Page generated by SRI International Pathway Tools version 19.5 on Sat Apr 30, 2016, BIOCYC11A.