EzCatDB: T00242
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DB codeT00242
CATH domainDomain 13.50.50.60 : FAD/NAD(P)-binding domainCatalytic domain
Domain 23.50.50.60 : FAD/NAD(P)-binding domainCatalytic domain
Domain 33.30.390.30 : Enolase-like; domain 1Catalytic domain
E.C.1.8.1.12

CATH domainRelated DB codes (homologues)
3.30.390.30 : Enolase-like; domain 1M00163,T00017,T00213,T00233
3.50.50.60 : FAD/NAD(P)-binding domainM00163,D00015,D00041,D00042,D00045,D00064,D00071,T00004,T00015,T00017,T00025,T00211,T00213,T00233

Enzyme Name
UniProtKBKEGG

P39040P28593
Protein nameTrypanothione reductase (TR) (EC 1.8.1.12) (N(1),NTrypanothione reductase (TR) (EC 1.8.1.12) (N(1),Ntrypanothione-disulfide reductase
trypanothione reductase
NADPH2:trypanothione oxidoreductase
Synonyms8)-bis(glutathionyl)spermidine reductase
8)-bis(glutathionyl)spermidine reductase
PfamPF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
PF02852 (Pyr_redox_dim)
[Graphical view]
PF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
PF02852 (Pyr_redox_dim)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00480Glutathione metabolism

UniProtKB:Accession NumberP39040P28593
Entry nameTYTR_CRIFATYTR_TRYCR
ActivityTrypanothione + NADP(+) = trypanothione disulfide + NADPH.Trypanothione + NADP(+) = trypanothione disulfide + NADPH.
SubunitHomodimer.Homodimer.
Subcellular locationCytoplasm.Cytoplasm.
CofactorBinds 1 FAD per subunit.Binds 1 FAD per subunit.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProductsintermediates
KEGG-idC00016C00005C03170C00080C00006C02090
CompoundFADNADPHOxidized trypanothioneH+NADP+TrypanothioneEnzyme-Trypanothine complex
Typeamide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,nucleotideamide group,amine group,nucleotideamino acids,amine group,disulfide bond,lipid,peptide/proteinothersamide group,amine group,nucleotideamino acids,amine group,lipid,peptide/protein,sulfhydryl group
ChEBI16238
16474
35490
15378
18009
17842

PubChem643975
5884
115098
1038
5886
449517

               
1aogA01Bound:FADUnboundUnbound UnboundUnbound 
1aogB01Bound:FADUnboundUnbound UnboundUnbound 
1bzlA01Bound:FADUnboundBound:GCG UnboundUnbound 
1bzlB01Bound:FADUnboundBound:GCG UnboundUnbound 
1feaA01Bound:FADUnboundUnbound UnboundUnbound 
1feaB01Bound:FADUnboundUnbound UnboundUnbound 
1feaC01Bound:FADUnboundUnbound UnboundUnbound 
1feaD01Bound:FADUnboundUnbound UnboundUnbound 
1febA01Bound:FADUnboundUnbound UnboundUnbound 
1febB01Bound:FADUnboundUnbound UnboundUnbound 
1fecA01Bound:FADUnboundUnbound UnboundUnbound 
1fecB01Bound:FADUnboundUnbound UnboundUnbound 
1gxfA01Bound:FADUnboundUnbound UnboundUnboundIntermediate-analogue:QUM 502
1gxfB01Bound:FADUnboundUnbound UnboundUnboundIntermediate-analogue:QUM 502
1ndaA01Bound:FADUnboundUnbound UnboundUnbound 
1ndaB01Bound:FADUnboundUnbound UnboundUnbound 
1ndaC01Bound:FADUnboundUnbound UnboundUnbound 
1ndaD01Bound:FADUnboundUnbound UnboundUnbound 
1typA01Bound:FADUnboundAnalogue:SPD-GSH-GSH-SPD UnboundUnbound 
1typB01Bound:FADUnboundAnalogue:SPD-GSH-GSH-SPD UnboundUnbound 
1tytA01Bound:FADUnboundUnbound UnboundUnbound 
1tytB01Bound:FADUnboundUnbound UnboundUnbound 
2tprA01Bound:FADUnboundUnbound UnboundUnbound 
2tprB01Bound:FADUnboundUnbound UnboundUnbound 
1aogA02UnboundUnboundUnbound UnboundUnbound 
1aogB02UnboundUnboundUnbound UnboundUnbound 
1bzlA02UnboundUnboundUnbound UnboundUnbound 
1bzlB02UnboundUnboundUnbound UnboundUnbound 
1feaA02UnboundUnboundUnbound UnboundUnbound 
1feaB02UnboundUnboundUnbound UnboundUnbound 
1feaC02UnboundUnboundUnbound UnboundUnbound 
1feaD02UnboundUnboundUnbound UnboundUnbound 
1febA02UnboundUnboundUnbound UnboundUnbound 
1febB02UnboundUnboundUnbound UnboundUnbound 
1fecA02UnboundUnboundUnbound UnboundUnbound 
1fecB02UnboundUnboundUnbound UnboundUnbound 
1gxfA02UnboundUnboundUnbound UnboundUnbound 
1gxfB02UnboundUnboundUnbound UnboundUnbound 
1ndaA02UnboundUnboundUnbound UnboundUnbound 
1ndaB02UnboundUnboundUnbound UnboundUnbound 
1ndaC02UnboundUnboundUnbound UnboundUnbound 
1ndaD02UnboundUnboundUnbound UnboundUnbound 
1typA02UnboundUnboundUnbound Bound:NAPUnbound 
1typB02UnboundUnboundUnbound Bound:NAPUnbound 
1tytA02UnboundUnboundUnbound UnboundUnbound 
1tytB02UnboundUnboundUnbound UnboundUnbound 
2tprA02UnboundUnboundUnbound UnboundUnbound 
2tprB02UnboundUnboundUnbound UnboundUnbound 
1aogA03UnboundUnboundUnbound UnboundUnbound 
1aogB03UnboundUnboundUnbound UnboundUnbound 
1bzlA03UnboundUnboundUnbound UnboundUnbound 
1bzlB03UnboundUnboundUnbound UnboundUnbound 
1feaA03UnboundUnboundUnbound UnboundUnbound 
1feaB03UnboundUnboundUnbound UnboundUnbound 
1feaC03UnboundUnboundUnbound UnboundUnbound 
1feaD03UnboundUnboundUnbound UnboundUnbound 
1febA03UnboundUnboundUnbound UnboundUnbound 
1febB03UnboundUnboundUnbound UnboundUnbound 
1fecA03UnboundUnboundUnbound UnboundUnbound 
1fecB03UnboundUnboundUnbound UnboundUnbound 
1gxfA03UnboundUnboundUnbound UnboundUnbound 
1gxfB03UnboundUnboundUnbound UnboundUnbound 
1ndaA03UnboundUnboundUnbound UnboundUnbound 
1ndaB03UnboundUnboundUnbound UnboundUnbound 
1ndaC03UnboundUnboundUnbound UnboundUnbound 
1ndaD03UnboundUnboundUnbound UnboundUnbound 
1typA03UnboundUnboundUnbound UnboundUnbound 
1typB03UnboundUnboundUnbound UnboundUnbound 
1tytA03UnboundUnboundUnbound UnboundUnbound 
1tytB03UnboundUnboundUnbound UnboundUnbound 
2tprA03UnboundUnboundUnbound UnboundUnbound 
2tprB03UnboundUnboundUnbound UnboundUnbound 

Active-site residues
resource
Swiss-prot;P39040, P28593 & literature [7], [16], [23]
pdbCatalytic residuescomment
          
1aogA01CYS 53;CYS 58;LYS 61
disulfide bonded/oxidized form C53-C58
1aogB01CYS 53;CYS 58;LYS 61
disulfide bonded/oxidized form C53-C58
1bzlA01CYS 53;CYS 58;LYS 61
disulfide bonded/oxidized form C53-C58
1bzlB01CYS 53;CYS 58;LYS 61
disulfide bonded/oxidized form C53-C58
1feaA01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1feaB01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1feaC01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1feaD01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1febA01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1febB01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1fecA01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1fecB01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1gxfA01CYS 53;CYS 58;LYS 61
reduced form C53, C58
1gxfB01CYS 53;CYS 58;LYS 61
reduced form C53, C58
1ndaA01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
1ndaB01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
1ndaC01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
1ndaD01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
1typA01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
1typB01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
1tytA01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
1tytB01CYS 52;CYS 57;LYS 60
disulfide bonded/oxidized form C52-C57
2tprA01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
2tprB01CYS 51;CYS 56;LYS 59
disulfide bonded/oxidized form C51-C56
1aogA02GLU 203
 
1aogB02GLU 203
 
1bzlA02GLU 203
 
1bzlB02GLU 203
 
1feaA02GLU 201
 
1feaB02GLU 201
 
1feaC02GLU 201
 
1feaD02GLU 201
 
1febA02GLU 201
 
1febB02GLU 201
 
1fecA02GLU 201
 
1fecB02GLU 201
 
1gxfA02GLU 203
 
1gxfB02GLU 203
 
1ndaA02GLU 202
 
1ndaB02GLU 202
 
1ndaC02GLU 202
 
1ndaD02GLU 202
 
1typA02GLU 202
 
1typB02GLU 202
 
1tytA02GLU 202
 
1tytB02GLU 202
 
2tprA02GLU 201
 
2tprB02GLU 201
 
1aogA03HIS 461;GLU 466
 
1aogB03HIS 461;GLU 466
 
1bzlA03HIS 461;GLU 466
 
1bzlB03HIS 461;GLU 466
 
1feaA03HIS 460;GLU 465
 
1feaB03HIS 460;GLU 465
 
1feaC03HIS 460;GLU 465
 
1feaD03HIS 460;GLU 465
 
1febA03HIS 460;GLU 465
 
1febB03HIS 460;GLU 465
 
1fecA03HIS 460;GLU 465
 
1fecB03HIS 460;GLU 465
 
1gxfA03HIS 461;GLU 466
 
1gxfB03HIS 461;GLU 466
 
1ndaA03HIS 460;GLU 465
 
1ndaB03HIS 460;GLU 465
 
1ndaC03HIS 460;GLU 465
 
1ndaD03HIS 460;GLU 465
 
1typA03HIS 461;GLU 466
 
1typB03HIS 461;GLU 466
 
1tytA03HIS 461;GLU 466
 
1tytB03HIS 461;GLU 466
 
2tprA03HIS 460;GLU 465
 
2tprB03HIS 460;GLU 465
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]Fig.1, p.315
[5]

[6]p.8766-8767
[7]p.329-332
[8]p.3092-3094
[9]

[12]p.147-151
[13]

[15]

[17]p.55-57
[23]


references
[1]
PubMed ID2666188
JournalBiochem Soc Trans
Year1989
Volume17
Pages315-7
AuthorsKrauth-Siegel RL, Jockers-Scherubl MC, Becker K, Schirmer RH
TitleNADPH-dependent disulphide reductases.
[2]
PubMed ID2254926
JournalJ Mol Biol
Year1990
Volume216
Pages235-7
AuthorsHunter WN, Smith K, Derewenda Z, Harrop SJ, Habash J, Islam MS, Helliwell JR, Fairlamb AH
TitleInitiating a crystallographic study of trypanothione reductase.
[3]
PubMed ID2231707
JournalJ Mol Biol
Year1990
Volume215
Pages335-7
AuthorsKuriyan J, Wong L, Guenther BD, Murgolo NJ, Cerami A, Henderson GB
TitlePreliminary crystallographic analysis of trypanothione reductase from Crithidia fasciculata.
[4]
PubMed ID2059620
JournalBiochemistry
Year1991
Volume30
Pages6124-7
AuthorsBradley M, Bucheler US, Walsh CT
TitleRedox enzyme engineering: conversion of human glutathione reductase into a trypanothione reductase.
[5]
PubMed ID2007114
JournalBiochemistry
Year1991
Volume30
Pages2761-7
AuthorsSullivan FX, Sobolov SB, Bradley M, Walsh CT
TitleMutational analysis of parasite trypanothione reductase: acquisition of glutathione reductase activity in a triple mutant.
[6]
CommentsX-ray crystallography
PubMed ID1924336
JournalProc Natl Acad Sci U S A
Year1991
Volume88
Pages8764-8
AuthorsKuriyan J, Kong XP, Krishna TS, Sweet RM, Murgolo NJ, Field H, Cerami A, Henderson GB
TitleX-ray structure of trypanothione reductase from Crithidia fasciculata at 2.4-A resolution.
Related PDB2tpr
[7]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS)
Medline ID92395672
PubMed ID1522596
JournalJ Mol Biol
Year1992
Volume227
Pages322-33
AuthorsHunter WN, Bailey S, Habash J, Harrop SJ, Helliwell JR, Aboagye-Kwarteng T, Smith K, Fairlamb AH
TitleActive site of trypanothione reductase. A target for rational drug design.
Related UniProtKBP39040
[8]
PubMed ID1453951
JournalMol Microbiol
Year1992
Volume6
Pages3089-99
AuthorsAboagye-Kwarteng T, Smith K, Fairlamb AH
TitleMolecular characterization of the trypanothione reductase gene from Crithidia fasciculata and Trypanosoma brucei: comparison with other flavoprotein disulphide oxidoreductases with respect to substrate specificity and catalytic mechanism.
[9]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS)
Medline ID93238745
PubMed ID8477734
JournalEur J Biochem
Year1993
Volume213
Pages67-75
AuthorsBailey S, Smith K, Fairlamb AH, Hunter WN
TitleSubstrate interactions between trypanothione reductase and N1-glutathionylspermidine disulphide at 0.28-nm resolution.
Related PDB1typ
Related UniProtKBP39040
[10]
PubMed ID8428618
JournalFEBS Lett
Year1993
Volume317
Pages105-8
AuthorsKrauth-Siegel RL, Sticherling C, Jost I, Walsh CT, Pai EF, Kabsch W, Lantwin CB
TitleCrystallization and preliminary crystallographic analysis of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease.
[11]
PubMed ID8371273
JournalJ Mol Biol
Year1993
Volume232
Pages1217-20
AuthorsZhang Y, Bailey S, Naismith JH, Bond CS, Habash J, McLaughlin P, Papiz MZ, Borges A, Cunningham M, Fairlamb AH, et al
TitleTrypanosoma cruzi trypanothione reductase. Crystallization, unit cell dimensions and structure solution.
[12]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS)
JournalActa Crystallogr D Biol Crystallogr
Year1994
Volume50
Pages139-54
AuthorsBailey S, Fairlamb AH, Hunter WN
TitleStructure of trypanothione reductase from Crithidia fasciculata at 2.6-A resolution; enzyme-NADP interactions at 2.8-A resolution
Related PDB1tyt
Related UniProtKBP39040
[13]
CommentsX-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS)
Medline ID94211757
PubMed ID8159665
JournalProteins
Year1994
Volume18
Pages161-73
AuthorsLantwin CB, Schlichting I, Kabsch W, Pai EF, Krauth-Siegel RL
TitleThe structure of Trypanosoma cruzi trypanothione reductase in the oxidized and NADPH reduced state.
Related UniProtKBP28593
[14]
CommentsX-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS)
JournalActa Crystallogr D Biol Crystallogr
Year1995
Volume51
Pages337-41
AuthorsStrickland CL, Puchalski R, Savvides SN, Karplus PA
TitleOverexpression of Crithidia fasciculata trypanothione reductase and crystallization using a novel geometry.
Related UniProtKBP39040
[15]
PubMed ID7548022
JournalBiochemistry
Year1995
Volume34
Pages12697-703
AuthorsZheng R, Cenas N, Blanchard JS
TitleCatalytic and potentiometric characterization of E201D and E201Q mutants of Trypanosoma congolense trypanothione reductase.
[16]
PubMed ID7672506
JournalFASEB J
Year1995
Volume9
Pages1138-46
AuthorsKrauth-Siegel RL, Schoneck R
TitleFlavoprotein structure and mechanism. 5. Trypanothione reductase and lipoamide dehydrogenase as targets for a structure-based drug design.
[17]
CommentsX-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS)
Medline ID96367082
PubMed ID8771196
JournalProtein Sci
Year1996
Volume5
Pages52-61
AuthorsZhang Y, Bond CS, Bailey S, Cunningham ML, Fairlamb AH, Hunter WN
TitleThe crystal structure of trypanothione reductase from the human pathogen Trypanosoma cruzi at 2.3 A resolution.
Related PDB1aog
Related UniProtKBP28593
[18]
PubMed ID8628734
JournalProteins
Year1996
Volume24
Pages73-80
AuthorsJacoby EM, Schlichting I, Lantwin CB, Kabsch W, Krauth-Siegel RL
TitleCrystal structure of the Trypanosoma cruzi trypanothione reductase.mepacrine complex.
[19]
PubMed ID9174360
JournalBiochemistry
Year1997
Volume36
Pages6437-47
AuthorsStoll VS, Simpson SJ, Krauth-Siegel RL, Walsh CT, Pai EF
TitleGlutathione reductase turned into trypanothione reductase: structural analysis of an engineered change in substrate specificity.
[20]
PubMed ID9057833
JournalEur J Biochem
Year1997
Volume243
Pages690-4
AuthorsMarsh IR, Bradley M
TitleSubstrate specificity of trypanothione reductase.
[21]
PubMed ID9309766
JournalParasitology
Year1997
Volume114 Suppl
PagesS17-29
AuthorsHunter WN
TitleA structure-based approach to drug discovery; crystallography and implications for the development of antiparasite drugs.
[22]
PubMed ID9986706
JournalJ Med Chem
Year1999
Volume42
Pages364-72
AuthorsGallwitz H, Bonse S, Martinez-Cruz A, Schlichting I, Schumacher K, Krauth-Siegel RL
TitleAjoene is an inhibitor and subversive substrate of human glutathione reductase and Trypanosoma cruzi trypanothione reductase: crystallographic, kinetic, and spectroscopic studies.
[23]
CommentsX-ray crystallography
PubMed ID10368274
JournalStructure Fold Des
Year1999
Volume7
Pages81-9
AuthorsBond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH, Hunter WN
TitleCrystal structure of Trypanosoma cruzi trypanothione reductase in complex with trypanothione, and the structure-based discovery of new natural product inhibitors.
Related PDB1bzl
[24]
PubMed ID10968268
JournalBioorg Med Chem
Year2000
Volume8
Pages95-103
AuthorsBonnet B, Soullez D, Girault S, Maes L, Landry V, Davioud-Charvet E, Sergheraert C
TitleTrypanothione reductase inhibition/trypanocidal activity relationships in a 1,4-bis(3-aminopropyl)piperazine series.
[25]
PubMed ID11170645
JournalJ Med Chem
Year2001
Volume44
Pages548-65
AuthorsSalmon-Chemin L, Buisine E, Yardley V, Kohler S, Debreu MA, Landry V, Sergheraert C, Croft SL, Krauth-Siegel RL, Davioud-Charvet E
Title2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity.
[26]
PubMed ID11867629
JournalJ Biol Chem
Year2002
Volume277
Pages17548-55
AuthorsReckenfelderbaumer N, Krauth-Siegel RL
TitleCatalytic properties, thiol pK value, and redox potential of Trypanosoma brucei tryparedoxin.
[27]
PubMed ID12111385
JournalJ Mol Model (Online)
Year2002
Volume8
Pages173-83
AuthorsIribarne F, Paulino M, Aguilera S, Murphy M, Tapia O
TitleDocking and molecular dynamics studies at trypanothione reductase and glutathione reductase active sites.
[28]
PubMed ID15102853
JournalJ Biol Chem
Year2004
Volume279
Pages29493-500
AuthorsSaravanamuthu A, Vickers TJ, Bond CS, Peterson MR, Hunter WN, Fairlamb AH
TitleTwo interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: a template for drug design.
Related PDB1gxf

comments
As in its homologous enzymes (thioredoxin reductase; D00045 & dihydrolipoyl dehydrogenase; T00017 in EzCatDB), this enzyme catalyzes three distinct redox reactions;
(A) Hydride or electron transfer from NADPH to FAD (Reduction of FAD by NADPH) (part of reductive half-reaction)
(B) Electron transfer from reduced FAD (FADH2) to active-site disulfide (Cys-Cys) (part of reductive half-reaction)
(C) Electron transfer from active site cysteine residues to trypanothione disulfide substrate (Reduction of substrate [trypanothione disulfide] at the active site)

createdupdated
2004-12-242009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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