Ligand glutathionylspermidine

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Basic Ligand Information

Molecular Structure

Picture of glutathionylspermidine (click for magnification)

Molecular Formula

BRENDA Name

InChIKey

C₁₇H₃₄N₆O₅S

glutathionylspermidine

NEDQLXHBVHSKNV-STQMWFEESA-N

Synonyms:

N-[3-[(4-aminobutyl)amino]propyl]-L-gamma-glutamyl-L-cysteinylglycine, N1-(gamma-Glu-L-Cys-Gly)-spermidine, N1-(gamma-L-Glu-L-Cys-Gly)-spermidine, N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine, N1-glutathionylspermidine

Pathway Source

Pathways

BRENDA

glutathione metabolism

KEGG

Glutathione metabolism

MetaCyc

glutathionylspermidine biosynthesis, trypanothione biosynthesis

Show all BRENDA pathways known for glutathionylspermidine

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Roles as Enzyme Ligand

In Vivo Substrate in Enzyme-catalyzed Reactions (7 results)

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Show Natural Substrate (7 entries)

EC NUMBER

PROVEN IN VIVO REACTION

REACTION DIAGRAM

LITERATURE

ENZYME 3D STRUCTURE

3.5.1.78

glutathionylspermidine + H2O = glutathione + spermidine

31903, 716863, 727554, 727627

3a2y, 3D-view

3.5.1.78

glutathionylspermidine + H2O = glutathione + spermidine

31903, 716863, 727554, 727627

glutathionylspermidine + methylglyoxal = ?

692049

6.3.1.9

glutathione + glutathionylspermidine + ATP = N1,N8-bis(glutathionyl)spermidine + ADP + phosphate

744910, 662446, 746173, 744964, 746270, 661810, 662802, 661011

6.3.1.9

gamma-L-Glu-L-Cys-Gly + N1-(gamma-Glu-L-Cys-Gly)-spermidine + ATP = N1,N8-bis-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ADP + phosphate

965, 964

6.3.1.9

gamma-L-glutamyl-L-cysteinyl-glycine + N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ATP = N1,N8-bis-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ADP + phosphate

650657, 652306

6.3.1.9

N1-glutathionylspermidine + glutathione + ATP = N1,N8-bis(glutathionyl)spermidine + ADP + phosphate

727951, 728592

6.3.1.9

4 entries

In Vivo Product in Enzyme-catalyzed Reactions (4 results)

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Show Natural Product (4 entries)

EC NUMBER

PROVEN IN VIVO REACTION

REACTION DIAGRAM

LITERATURE

ENZYME 3D STRUCTURE

6.3.1.8

glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate

3a2y, 3D-view

6.3.1.8

glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate

3o98, 3D-view

6.3.1.9

glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate

6.3.1.9

glutathione + spermidine + ATP = N1-glutathionylspermidine + N8-glutathionylspermidine + ADP + phosphate

Substrate in Enzyme-catalyzed Reactions (13 results)

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EC NUMBER

REACTION

REACTION DIAGRAM

LITERATURE

ENZYME 3D STRUCTURE

3.5.1.78

glutathionylspermidine + H2O = glutathione + spermidine

967, 968, 969, 31903, 649733, 712459, 716863, 727554, 727627

3a2y, 3D-view

3.5.1.78

glutathionylspermidine + H2O = glutathione + spermidine

967, 968, 969, 31903, 649733, 712459, 716863, 727554, 727627

3o98, 3D-view

4.4.1.5

glutathionylspermidine + methylglyoxal = ?

692049, 678043

4.4.1.5

glutathionylspermidine + phenylglyoxal = ?

678043

4.4.1.5

N1-glutathionylspermidine + methylglyoxal = ?

681984

6.3.1.8

glutathionylspermidine + H2O = glutathione + spermidine

649733

3a2y, 3D-view

6.3.1.8

glutathionylspermidine + H2O = glutathione + spermidine

649733

3o98, 3D-view

6.3.1.9

glutathione + glutathionylspermidine + ATP = N1,N8-bis(glutathionyl)spermidine + ADP + phosphate

744910, 662446, 746173, 744964, 746270, 661810, 662802, 661011

6.3.1.9

gamma-L-Glu-L-alpha-aminobutyrylglycine + N1-(gamma-Glu-L-Cys-Gly)-spermidine + ATP = ?

964

6.3.1.9

gamma-L-Glu-L-Cys-Gly + N1-(gamma-Glu-L-Cys-Gly)-spermidine + ATP + H2O = N1,N8-bis-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate + NH3

963, 964, 971

6.3.1.9

gamma-L-Glu-L-Cys-Gly + N1-(gamma-Glu-L-Cys-Gly)-spermidine + ATP = N1,N8-bis-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ADP + phosphate

965, 964

6.3.1.9

gamma-L-glutamyl-L-cysteinyl-glycine + N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ATP = N1,N8-bis-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ADP + phosphate

650657, 652306

6.3.1.9

N1-glutathionylspermidine + glutathione + ATP = N1,N8-bis(glutathionyl)spermidine + ADP + phosphate

Product in Enzyme-catalyzed Reactions (10 results)

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EC NUMBER

REACTION

REACTION DIAGRAM

LITERATURE

ENZYME 3D STRUCTURE

3.5.1.78

trypanothione + H2O = glutathione + glutathionylspermidine

, 649733

3a2y, 3D-view

3.5.1.78

trypanothione + H2O = glutathione + glutathionylspermidine

, 649733

3o98, 3D-view

6.3.1.8

glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate

3a2y, 3D-view

6.3.1.8

glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate

3o98, 3D-view

6.3.1.8

gamma-L-Glu-L-Cys-Gly + spermidine + ATP = N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate

962, 967, 968, 963, 964, 965, 966

3a2y, 3D-view

6.3.1.8

gamma-L-Glu-L-Cys-Gly + spermidine + ATP = N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate

962, 967, 968, 963, 964, 965, 966

3o98, 3D-view

6.3.1.8

gamma-L-Glu-L-Cys-Gly + spermidine + MgATP2- = N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + MgADP- + phosphate

965, 649733, 650561

3a2y, 3D-view

6.3.1.8

gamma-L-Glu-L-Cys-Gly + spermidine + MgATP2- = N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + MgADP- + phosphate

965, 649733, 650561

3o98, 3D-view

6.3.1.9

glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate

6.3.1.9

glutathione + spermidine + ATP = N1-glutathionylspermidine + N8-glutathionylspermidine + ADP + phosphate

3D Structure of Enzyme-Ligand-Complex (PDB) (24 results)

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EC NUMBER

ENZYME 3D STRUCTURE

Enzyme Kinetic Parameters

k_cat Value (Turnover Number) (8 results)

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EC NUMBER

TURNOVER NUMBER [1/S]

TURNOVER NUMBER MAXIMUM [1/S]

COMMENTARY

LITERATURE

2.1

105

with phenylglyoxal

678043

4.4.1.5

161

with methylglyoxal

1590

2.8

pH 8.0

652306

6.3.1.9

8.7

pH 7.2, 25°C, recombinant trypanothione synthase

K_M Value (15 results)

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EC NUMBER

KM VALUE [MM]

KM VALUE MAXIMUM [MM]

COMMENTARY

LITERATURE

3.5.1.78

0.5

pH 7.3, amidase activity

0.9

5.5

C173A mutant amidase fragment

31903

4.4.1.5

0.008

with methylglyoxal

678043

4.4.1.5

0.014

with phenylglyoxal

0.064

0.148

0.5

pH 7.3, 25°C, amidase activity

649733

6.3.1.9

0.012

recombinant enzyme, pH 8.0, 25°C, HEPES buffer

727951

6.3.1.9

0.016

recombinant enzyme, pH 8.0, 37°C, HEPES buffer

0.02

0.032

recombinant enzyme, pH 7.0, 37°C, phosphate buffer

727951

6.3.1.9

0.04

pH 7.7, 25°C, recombinant trypanothione synthase

662802

6.3.1.9

0.066

pH 8.0

652306

6.3.1.9

0.48

pH 7.2, 25°C, recombinant trypanothione synthase

662446

6.3.1.9

7 entries

References & Links

Literature References (31)

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BRENDA REFERENCE ID

PUBMED ID

TITLE

YEAR

AUTHORS

JOURNAL

VOLUME

PAGES

962

Glutathionylspermidine synthetase

1971

Tabor, H.; Tabor, C.W.

Methods Enzymol.

815-817

963

Biochemical studies on protein folding chaperones (HSP90 and cyclophilin) and on trypanosomal enzymes (trypanothione and glutathionylspermidine synthetases) (heat shock protein)

1995

Nadeau, K.C.

Diss. Abstr. Int. B

3744

964

1304372

Purification of glutathionylspermidine and trypanothione synthetase from Crithidia fasciculata

1992

Smith, K.; Nadeau, K.; Bradley, M.; Walsh, C.; Fairlamb, A.H.

Protein Sci.

874-883

965

9677355

Cloning and characterization of the two enzymes responsible for trypanothione biosynthesis in Crithidia fasciculata

1998

Tetaud, E.; Manai, F.; Barrett, M.P.; Nadeau, K.; Walsh, C.T.; Fairlamb, A.H.

J. Biol. Chem.

273

19383-19390

966

9041518

Characterization of the peptide substrate specificity of glutathionylspermidine synthetase from Crithidia fasciculata

1997

De Craecker, S.; Verbruggen, C.; Rajan, P.; Smith, K.; Haemers, A.; Fairlamb, A.H.

Mol. Biochem. Parasitol.

25-32

967

9384533

Aldehyde and phosphinate analogs of glutathione and glutathionylspermidine: potent, selective binding inhibitors of the E. coli bifunctional glutathionylspermidine synthetase/amidase

1997

Lin, C.H.; Chen, S.; Kwon, D.S.; Coward, J.K.; Walsh, C.T.

Chem. Biol.

859-866

968

9371250

Design, synthesis, and biochemical evaluation of phosphonate and phosphonamidate analogs of glutathionylspermidine as inhibitors of glutathionylspermidine synthetase/amidase from Escherichia coli

1997

Chen, S.; Lin, C.H.; Kwon, D.S.; Walsh, C.T.; Coward, J.K.

J. Med. Chem.

3842-3850

969

7775463

Glutathionylspermidine metabolism in Escherichia coli. Purification, cloning, overproduction, and characterization of a bifunctional glutathionylspermidine synthetase/amidase

1995

Bollinger, J.M.; Kwon, D.S.; Huisman, G.W.; Kolter, R.; Walsh, C.T.

J. Biol. Chem.

270

14031-14041

971

2354163

Biosynthesis of the trypanosomatid metabolite trypanothione: purification and characterization of trypanothione synthetase from Crithidia fasciculata

1990

Henderson, G.B.; Yamaguchi, M.; Novoa, L.; Fairlamb, A.H.; Cerami, A.

Biochemistry

3924-3929

31903

9398217

Evidence for a glutathionyl-enzyme intermediate in the amidase activity of the bifunctional glutathionylspermidine synthetase/amidase from Escherichia coli

1997

Lin, C.H.; Kwon, D.S.; Bollinger, J.M.; Walsh, C.T.

Biochemistry

14930-14938

649733

12049631

Characterization of recombinant glutathionylspermidine synthetase/amidase from Crithidia fasciculata

2002

Oza, S.L.; Ariyanayagam, M.R.; Fairlamb, A.H.

Biochem. J.

364

679-686

650561

12217358

Glutathione-like tripeptides as inhibitors of glutathionylspermidine synthetase. Part 2: Substitution of the glycine part

2002

Amssoms, K.; Oza, S.L.; Augustyns, K.; Yamani, A.; Lambeir, A.M.; Bal, G.; Van der Veken, P.; Fairlamb, A.H.; Haemers, A.

Bioorg. Med. Chem. Lett.

2703-2705

650657

Detection by HPLC of a trypanothione synthetase activity in vitro from Entamoeba histolytica

1999

Ondarza, R.N.; Hernandez, E.; Iturbe, A.; Hurtado, G.; Tamayo, E.M.

Biotechnol. Appl. Biochem.

41-45

652306

12121990

A Single Enzyme Catalyses Formation of Trypanothione from Glutathione and Spermidine in Trypanosoma cruzi

2002

Oza, S.L.; Tetaud, E.; Ariyanayagam, M.R.; Warnon, S.S.; Fairlamb, A.H.

J. Biol. Chem.

277

35853-35861

661011

16008527

Phenotypic analysis of trypanothione synthetase knockdown in the African trypanosome

2005

Ariyanayagam, M.R.; Oza, S.L.; Guther, M.L.S.; Fairlamb, A.H.

Biochem. J.

391

425-432

661810

15110394

Valdiation of Trypanosoma brucei trypanothione synthetase as drug target

2004

Comini, M.A.; Guerrero, S.A.; Haile, S.; Menge, U.; Lunsdorf, H.; Flohe, L.

Free Radic. Biol. Med.

1289-1302

662446

15537651

Trypanothione synthesis in Crithidia revisited

2005

Comini, M.; Menge, U.; Wissing, J.; Flohe, L.

J. Biol. Chem.

280

6850-6860

662802

15610825

Trypanothione biosynthesis in Leishmania major

2005

Oza, S.L.; Shaw, M.P.; Wyllie, S.; Fairlamb, A.H.

Mol. Biochem. Parasitol.

139

107-116

678043

16958620

Trypanothione-dependent glyoxalase I in Trypanosoma cruzi

2006

Greig, N.; Wyllie, S.; Vickers, T.J.; Fairlamb, A.H.

Biochem. J.

400

217-223

681984

16430697

Specificity of the trypanothione-dependent Leishmania major glyoxalase I: structure and biochemical comparison with the human enzyme

2006

Ariza, A.; Vickers, T.J.; Greig, N.; Armour, K.A.; Dixon, M.J.; Eggleston, I.M.; Fairlamb, A.H.; Bond, C.S.

Mol. Microbiol.

1239-1248

692049

18533363

Microbial glyoxalase enzymes: metalloenzymes controlling cellular levels of methylglyoxal

2008

Sukdeo, N.; Honek, J.F.

Drug Metabol. Drug Interact.

29-50

712459

20530482

Protein S-thiolation by Glutathionylspermidine (Gsp): the role of Escherichia coli Gsp synthetase/amidase in redox regulation

2010

Chiang, B.Y.; Chen, T.C.; Pai, C.H.; Chou, C.C.; Chen, H.H.; Ko, T.P.; Hsu, W.H.; Chang, C.Y.; Wu, W.F.; Wang, A.H.; Lin, C.H.

J. Biol. Chem.

285

25345-25353

716863

21226054

Structure and mechanism of Escherichia coli glutathionylspermidine amidase belonging to the family of cysteine; histidine-dependent amidohydrolases/peptidases

2011

Pai, C.H.; Wu, H.J.; Lin, C.H.; Wang, A.H.

Protein Sci.

557-566

727554

23106382

Escherichia coli glutathionylspermidine synthetase/amidase: phylogeny and effect on regulation of gene expression

2013

Chattopadhyay, M.K.; Chen, W.; Tabor, H.

FEMS Microbiol. Lett.

338

132-140

727627

23097746

Comparison of the functions of glutathionylspermidine synthetase/amidase from E. coli and its predicted homologues YgiC and YjfC

2012

Sui, L.; Warren, J.C.; Russell, J.P.; Stourman, N.V.

Int. J. Biochem. Mol. Biol.

302-312

727951

23814051

Dissecting the catalytic mechanism of Trypanosoma brucei trypanothione synthetase by kinetic analysis and computational modeling

2013

Leroux, A.E.; Haanstra, J.R.; Bakker, B.M.; Krauth-Siegel, R.L.

J. Biol. Chem.

288

23751-23764

728592

23451087

Molecular dynamics reveal binding mode of glutathionylspermidine by trypanothione synthetase

2013

Koch, O.; Cappel, D.; Nocker, M.; Jaeger, T.; Flohe, L.; Sotriffer, C.A.; Selzer, P.M.

PLoS ONE

e56788

744910

29127710

Buthionine sulfoximine is a multitarget inhibitor of trypanothione synthesis in Trypanosoma cruzi

2017

Vazquez, C.; Mejia-Tlachi, M.; Gonzalez-Chavez, Z.; Silva, A.; Rodriguez-Zavala, J.S.; Moreno-Sanchez, R.; Saavedra, E.

FEBS Lett.

591

3881-3894

744964

24853758

Genetic and chemical analyses reveal that trypanothione synthetase but not glutathionylspermidine synthetase is essential for Leishmania infantum

2014

Sousa, A.F.; Gomes-Alves, A.G.; Benitez, D.; Comini, M.A.; Flohe, L.; Jaeger, T.; Passos, J.; Stuhlmann, F.; Tomas, A.M.; Castro, H.

Free Radic. Biol. Med.

229-238

746173

27070550

Identification of novel chemical scaffolds inhibiting trypanothione synthetase from pathogenic trypanosomatids

2016

Benitez, D.; Medeiros, A.; Fiestas, L.; Panozzo-Zenere, E.A.; Maiwald, F.; Prousis, K.C.; Roussaki, M.; Calogeropoulou, T.; Detsi, A.; Jaeger, T.; Sarlauskas, J.; Peterlin Masic, L.; Kunick, C.; Labadie, G.R.; Flohe, L.; Comini, M.A.

PLoS Negl. Trop. Dis.

e0004617

746270

24901644

Stage-dependent expression and up-regulation of trypanothione synthetase in amphotericin B resistant Leishmania donovani

2014

Equbal, A.; Suman, S.S.; Anwar, S.; Singh, K.P.; Zaidi, A.; Sardar, A.H.; Das, P.; Ali, V.

PLoS ONE

e97600