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 → Amines and Polyamines Biosynthesis|
|Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Reductants Biosynthesis|
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].
Unification Links: EcoCyc:PWY-4121
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
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
Chen97c: 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
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
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
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
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
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