DB code: D00045

CATH domain 3.50.50.60 : FAD/NAD(P)-binding domain
3.50.50.60 : FAD/NAD(P)-binding domain Catalytic domain
E.C. 1.8.1.9
CSA 1tde
M-CSA 1tde
MACiE

CATH domain Related DB codes (homologues)
3.50.50.60 : FAD/NAD(P)-binding domain M00163 D00015 D00041 D00042 D00064 D00071 T00004 T00015 T00017 T00025 T00211 T00213 T00233 T00242

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
Q39243 Thioredoxin reductase 1
EC 1.8.1.9
NADPH-dependent thioredoxin reductase 1
NTR 1
NP_195271.2 (Protein)
NM_119711.3 (DNA/RNA sequence)
PF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
[Graphical View]
P0A9P4 Thioredoxin reductase
TRXR
EC 1.8.1.9
NP_415408.1 (Protein)
NC_000913.2 (DNA/RNA sequence)
YP_489160.1 (Protein)
NC_007779.1 (DNA/RNA sequence)
PF00070 (Pyr_redox)
PF07992 (Pyr_redox_2)
[Graphical View]

KEGG enzyme name
thioredoxin-disulfide reductase
NADP-thioredoxin reductase
NADPH-thioredoxin reductase
thioredoxin reductase (NADPH)
NADPH2:oxidized thioredoxin oxidoreductase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
Q39243 TRXB1_ARATH Thioredoxin + NADP(+) = thioredoxin disulfide + NADPH. Homodimer. Cytoplasm. Binds 1 FAD per subunit.
P0A9P4 TRXB_ECOLI Thioredoxin + NADP(+) = thioredoxin disulfide + NADPH. Homodimer. Cytoplasm. Binds 1 FAD per subunit.

KEGG Pathways
Map code Pathways E.C.
MAP00240 Pyrimidine metabolism

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00016 C00005 C00343 C00080 C00006 C00342
E.C.
Compound FAD NADPH Oxidized thioredoxin H+ NADP+ Reduced thioredoxin
Type amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,nucleotide amide group,amine group,nucleotide amide group,carbohydrate,disulfide bond,peptide/protein others amide group,amine group,nucleotide amide group,carbohydrate,peptide/protein,sulfhydryl group
ChEBI 16238
 16238
 		16474
 16474
 		15378
 15378
 		18009
 18009
PubChem 643975
 643975
 		5884
 5884
 		1038
 1038
 		5886
 5886
1cl0A01 Bound:FAD Unbound Unbound Unbound Unbound
1f6mA01 Bound:FAD Unbound Unbound Unbound Unbound
1f6mB01 Bound:FAD Unbound Unbound Unbound Unbound
1f6mE01 Bound:FAD Unbound Unbound Unbound Unbound
1f6mF01 Bound:FAD Unbound Unbound Unbound Unbound
1tdeA01 Bound:FAD Unbound Unbound Unbound Unbound
1tdfA01 Bound:FAD Unbound Unbound Unbound Unbound
1trbA01 Bound:FAD Unbound Unbound Unbound Unbound
1vdcA01 Bound:FAD Unbound Unbound Unbound Unbound
1cl0A02 Unbound Unbound Unbound Unbound Unbound
1f6mA02 Unbound Unbound Unbound Analogue:3AA Analogue:CYS_32-SER_35(chain C)
1f6mB02 Unbound Unbound Unbound Analogue:3AA Analogue:CYS_32-SER_35(chain D)
1f6mE02 Unbound Unbound Unbound Analogue:3AA Analogue:CYS_32-SER_35(chain G)
1f6mF02 Unbound Unbound Unbound Analogue:3AA Analogue:CYS_32-SER_35(chain H)
1tdeA02 Unbound Unbound Unbound Unbound Unbound
1tdfA02 Unbound Unbound Unbound Bound:NAP Unbound
1trbA02 Unbound Unbound Unbound Unbound Unbound
1vdcA02 Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
PDB;1vdc & literature [6]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1cl0A01
1f6mA01
1f6mB01
1f6mE01
1f6mF01
1tdeA01
1tdfA01
1trbA01
1vdcA01
1cl0A02 CYS 135;CYS 138;ASP 139
1f6mA02 ;CYS 138;ASP 139 mutant C135S
1f6mB02 ;CYS 138;ASP 139 mutant C135S
1f6mE02 ;CYS 138;ASP 139 mutant C135S
1f6mF02 ;CYS 138;ASP 139 mutant C135S
1tdeA02 CYS 135;CYS 138;ASP 139
1tdfA02 CYS 135;;ASP 139 mutant C138S
1trbA02 CYS 135;;ASP 139 mutant C138S
1vdcA02 CYS 135;CYS 138;ASP 139

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[4]
p.3153
[6]
p.810, p.813-815
[7]
Scheme 1, Scheme 2, Scheme 3, p.1271-1275
[8]
Fig.1, Scheme 1, Scheme 2, p.4708-4711
[11]
Scheme 1, p.373-374
[12]
Fig.1, Fig.2, p.2370-2373, p.2375
[16]
Fig.1
[17]
Fig.1

References
[1]
Resource
Comments
Medline ID
PubMed ID 2666412
Journal J Biol Chem
Year 1989
Volume 264
Pages 12752-3
Authors Kuriyan J, Wong L, Russel M, Model P
Title Crystallization and preliminary x-ray characterization of thioredoxin reductase from Escherichia coli.
Related PDB
Related UniProtKB
[2]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS)
Medline ID 91296031
PubMed ID 2067578
Journal Nature
Year 1991
Volume 352
Pages 172-4
Authors Kuriyan J, Krishna TS, Wong L, Guenther B, Pahler A, Williams CH Jr, Model P
Title Convergent evolution of similar function in two structurally divergent enzymes.
Related PDB 1trb
Related UniProtKB P0A9P4
[3]
Resource
Comments
Medline ID
PubMed ID 8440680
Journal J Biol Chem
Year 1993
Volume 268
Pages 3845-9
Authors Nikkola M, Gleason FK, Eklund H
Title Reduction of mutant phage T4 glutaredoxins by Escherichia coli thioredoxin reductase.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 8136348
Journal Biochemistry
Year 1994
Volume 33
Pages 3148-54
Authors Mulrooney SB, Williams CH Jr
Title Potential active-site base of thioredoxin reductase from Escherichia coli: examination of histidine245 and aspartate139 by site-directed mutagenesis.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 7989308
Journal J Biol Chem
Year 1994
Volume 269
Pages 31418-23
Authors Ohnishi K, Niimura Y, Yokoyama K, Hidaka M, Masaki H, Uchimura T, Suzuki H, Uozumi T, Kozaki M, Komagata K, et al
Title Purification and analysis of a flavoprotein functional as NADH oxidase from Amphibacillus xylanus overexpressed in Escherichia coli.
Related PDB
Related UniProtKB
[6]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS)
Medline ID 94157914
PubMed ID 8114095
Journal J Mol Biol
Year 1994
Volume 236
Pages 800-16
Authors Waksman G, Krishna TS, Williams CH Jr, Kuriyan J
Title Crystal structure of Escherichia coli thioredoxin reductase refined at 2 A resolution. Implications for a large conformational change during catalysis.
Related PDB 1tde 1tdf
Related UniProtKB P0A9P4
[7]
Resource
Comments
Medline ID
PubMed ID 7557016
Journal FASEB J
Year 1995
Volume 9
Pages 1267-76
Authors Williams CH Jr
Title Mechanism and structure of thioredoxin reductase from Escherichia coli.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 8664260
Journal Biochemistry
Year 1996
Volume 35
Pages 4704-12
Authors Lennon BW, Williams CH Jr
Title Enzyme-monitored turnover of Escherichia coli thioredoxin reductase: insights for catalysis.
Related PDB
Related UniProtKB
[9]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS)
Medline ID 97153339
PubMed ID 9000629
Journal J Mol Biol
Year 1996
Volume 264
Pages 1044-57
Authors Dai S, Saarinen M, Ramaswamy S, Meyer Y, Jacquot JP, Eklund H
Title Crystal structure of Arabidopsis thaliana NADPH dependent thioredoxin reductase at 2.5 A resolution.
Related PDB 1vdc
Related UniProtKB Q39243
[10]
Resource
Comments
Medline ID
PubMed ID 9482874
Journal Proc Natl Acad Sci U S A
Year 1998
Volume 95
Pages 2267-72
Authors Svergun DI, Richard S, Koch MH, Sayers Z, Kuprin S, Zaccai G
Title Protein hydration in solution: experimental observation by x-ray and neutron scattering.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 9521113
Journal Protein Sci
Year 1998
Volume 7
Pages 369-75
Authors Veine DM, Ohnishi K, Williams CH Jr
Title Thioredoxin reductase from Escherichia coli: evidence of restriction to a single conformation upon formation of a crosslink between engineered cysteines.
Related PDB
Related UniProtKB
[12]
Resource
Comments X-RAY CRYSTALLOGRAPHY
Medline ID 20060988
PubMed ID 10595539
Journal Protein Sci
Year 1999
Volume 8
Pages 2366-79
Authors Lennon BW, Williams CH Jr, Ludwig ML
Title Crystal structure of reduced thioredoxin reductase from Escherichia coli: structural flexibility in the isoalloxazine ring of the flavin adenine dinucleotide cofactor.
Related PDB 1cl0
Related UniProtKB P0A9P4
[13]
Resource
Comments
Medline ID
PubMed ID 10913298
Journal Biochemistry
Year 2000
Volume 39
Pages 8859-69
Authors Reynolds CM, Poole LB
Title Attachment of the N-terminal domain of Salmonella typhimurium AhpF to Escherichia coli thioredoxin reductase confers AhpC reductase activity but does not affect thioredoxin reductase activity.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 10984401
Journal Biopolymers
Year 2000
Volume 54
Pages 489-500
Authors Renner C, Behrendt R, Sporlein S, Wachtveitl J, Moroder L
Title Photomodulation of conformational states. I. Mono- and bicyclic peptides with (4-amino)phenylazobenzoic acid as backbone constituent.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 10984402
Journal Biopolymers
Year 2000
Volume 54
Pages 501-14
Authors Renner C, Cramer J, Behrendt R, Moroder L
Title Photomodulation of conformational states. II. Mono- and bicyclic peptides with (4-aminomethyl)phenylazobenzoic acid as backbone constituent.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 11012662
Journal Eur J Biochem
Year 2000
Volume 267
Pages 6110-7
Authors Williams CH, Arscott LD, Muller S, Lennon BW, Ludwig ML, Wang PF, Veine DM, Becker K, Schirmer RH
Title Thioredoxin reductase two modes of catalysis have evolved.
Related PDB
Related UniProtKB
[17]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.95 ANGSTROMS) IN COMPLEX WITH TRXA
Medline ID 20407464
PubMed ID 10947986
Journal Science
Year 2000
Volume 289
Pages 1190-4
Authors Lennon BW, Williams CH Jr, Ludwig ML
Title Twists in catalysis: alternating conformations of Escherichia coli thioredoxin reductase.
Related PDB 1f6m
Related UniProtKB P0A9P4
[18]
Resource
Comments
Medline ID
PubMed ID 11567095
Journal Protein Sci
Year 2001
Volume 10
Pages 2037-49
Authors van den Berg PA, Mulrooney SB, Gobets B, van Stokkum IH, van Hoek A, Williams CH Jr, Visser AJ
Title Exploring the conformational equilibrium of E. coli thioredoxin reductase: characterization of two catalytically important states by ultrafast flavin fluorescence spectroscopy.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 12079785
Journal Chem Biol
Year 2002
Volume 9
Pages 731-40
Authors Cabrele C, Fiori S, Pegoraro S, Moroder L
Title Redox-active cyclic bis(cysteinyl)peptides as catalysts for in vitro oxidative protein folding.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 12379950
Journal Trends Parasitol
Year 2002
Volume 18
Pages 302-8
Authors Hirt RP, Muller S, Embley TM, Coombs GH
Title The diversity and evolution of thioredoxin reductase: new perspectives.
Related PDB
Related UniProtKB

Comments
There are two distinct types in thioredoxin reductase: large one (mammalian, Plasmodium falciparum) and small one (bacteria, plant) (see [16]). This enzyme corresponds to the small one.
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 (Cys135-Cys138)(part of reductive half-reaction)
(C) Electron transfer from active site cysteine residues to thioredoxin substrate (Reduction of substrate (thioredoxin) at the active site)
There are two active sites in this enzyme.
(a) Active site composed of Cys135/Cys138/Asp139: involved in reactions (B) & (C)
(b) Active site with Glu159: involved in reaction (A)
PDB structure 1f6m suggests the reactions (A) & (C), whilst the other structures indicate the reaction (B).

Created Updated
2004-03-24 2009-02-26