DB code: S00916

RLCP classification 3.676.249900.37 : Transfer
CATH domain 3.40.30.10 : Glutaredoxin Catalytic domain
E.C. 1.11.1.15
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
3.40.30.10 : Glutaredoxin S00279 M00184 D00866 D00869 D00870 D00278

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P65688 Putative peroxiredoxin Rv2238c/MT2298
EC 1.11.1.15
Thioredoxin reductase
NP_216754.1 (Protein)
NC_000962.3 (DNA/RNA sequence)
NP_336768.1 (Protein)
NC_002755.2 (DNA/RNA sequence)
YP_006515661.1 (Protein)
NC_018143.1 (DNA/RNA sequence)
PF00578 (AhpC-TSA)
[Graphical View]
Q5MYR6
Peroxiredoxin
XP_002808799.1 (Protein)
XM_002808753.1 (DNA/RNA sequence)
PF08534 (Redoxin)
[Graphical View]
Q8S3L0
Peroxiredoxin
PF08534 (Redoxin)
[Graphical View]

KEGG enzyme name
Peroxiredoxin
Thioredoxin peroxidase
Tryparedoxin peroxidase
Alkyl hydroperoxide reductase C22
AhpC
TrxPx
TXNPx
Prx
PRDX

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P65688 Y2238_MYCTU 2 R'-SH + ROOH = R'-S-S-R' + H2O + ROH.
Q5MYR6 Q5MYR6_PLAF7
Q8S3L0 Q8S3L0_9ROSI

KEGG Pathways
Map code Pathways E.C.
MAP00480 Glutathione metabolism

Compound table
Substrates Products Intermediates
KEGG-id C16736 C15498 C15496 C00001 C01335 I00142 I00143
E.C.
Compound R'-SH ROOH R'-S-S-R' H2O ROH Peptidyl-Cys-sulfenic acid Transient disulfide bond between peptidyl-Cys
Type sulfhydryl group others disulfide bond H2O carbohydrate
ChEBI 15377
PubChem 962
22247451
1xvwA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Intermediate-bound:CSO Unbound
1xvwB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Intermediate-bound:CSO Unbound
1xxuA00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound
1xxuB00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound
1xxuC00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound
1xxuD00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound
1xiyA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Intermediate-analogue:OCS Unbound
1xiyB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Intermediate-analogue:OCS Unbound
1tp9A00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound
1tp9B00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound
1tp9C00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound
1tp9D00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
Literature [4], [5], [6], [7], [9]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1xvwA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 42; ;ARG 116 CSO 45(S-hydroxycysteine) LEU 39;ILE 44;CSO 45
1xvwB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 42; ;ARG 116 CSO 45(S-hydroxycysteine) LEU 39;ILE 44;CSO 45
1xxuA00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 42;CYS 45;ARG 116 LEU 39;ILE 44;CYS 45
1xxuB00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 42;CYS 45;ARG 116 LEU 39;ILE 44;CYS 45
1xxuC00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 42;CYS 45;ARG 116 LEU 39;ILE 44;CYS 45
1xxuD00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 42;CYS 45;ARG 116 LEU 39;ILE 44;CYS 45
1xiyA Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 56; ;ARG 137 OCS 59(Cysteinesulfonic acid) GLY 53;THR 58;OCS 59
1xiyB Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 56; ;ARG 137 OCS 59(Cysteinesulfonic acid) GLY 53;THR 58;OCS 59
1tp9A00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 48;CYS 51;ARG 129 GLY 45;THR 50;CYS 51
1tp9B00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 48;CYS 51;ARG 129 GLY 45;THR 50;CYS 51
1tp9C00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 48;CYS 51;ARG 129 GLY 45;THR 50;CYS 51
1tp9D00 Pdbj logo s Rasmollogo id Rasmollogo chain Mmcif id Mmcif chain THR 48;CYS 51;ARG 129 GLY 45;THR 50;CYS 51

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
Fig. 4
[2]
Fig. 1
[6]
FIGURE 5

References
[1]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
Medline ID
PubMed ID 9587003
Journal Nat Struct Biol
Year 1998
Volume 5
Pages 400-6
Authors Choi HJ, Kang SW, Yang CH, Rhee SG, Ryu SE
Title Crystal structure of a novel human peroxidase enzyme at 2.0 A resolution.
Related PDB 1prx
Related UniProtKB P30041
[2]
Resource
Comments
Medline ID
PubMed ID 12517450
Journal Trends Biochem Sci
Year 2003
Volume 28
Pages 32-40
Authors Wood ZA, Schroder E, Robin Harris J, Poole LB
Title Structure, mechanism and regulation of peroxiredoxins.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 15697201
Journal Biochemistry
Year 2005
Volume 44
Pages 1755-67
Authors Echalier A, Trivelli X, Corbier C, Rouhier N, Walker O, Tsan P, Jacquot JP, Aubry A, Krimm I, Lancelin JM
Title Crystal structure and solution NMR dynamics of a D (type II) peroxiredoxin glutaredoxin and thioredoxin dependent: a new insight into the peroxiredoxin oligomerism.
Related PDB 1tp9
Related UniProtKB Q8S3L0
[4]
Resource
Comments
Medline ID
PubMed ID 15701515
Journal J Mol Biol
Year 2005
Volume 346
Pages 1035-46
Authors Li S, Peterson NA, Kim MY, Kim CY, Hung LW, Yu M, Lekin T, Segelke BW, Lott JS, Baker EN
Title Crystal Structure of AhpE from Mycobacterium tuberculosis, a 1-Cys peroxiredoxin.
Related PDB 1xvw 1xxu
Related UniProtKB P65688
[5]
Resource
Comments
Medline ID
PubMed ID 15701514
Journal J Mol Biol
Year 2005
Volume 346
Pages 1021-34
Authors Sarma GN, Nickel C, Rahlfs S, Fischer M, Becker K, Karplus PA
Title Crystal structure of a novel Plasmodium falciparum 1-Cys peroxiredoxin.
Related PDB 1xiy
Related UniProtKB Q5MYR6
[6]
Resource
Comments
Medline ID
PubMed ID 16916801
Journal J Biol Chem
Year 2006
Volume 281
Pages 31736-42
Authors Noguera-Mazon V, Lemoine J, Walker O, Rouhier N, Salvador A, Jacquot JP, Lancelin JM, Krimm I
Title Glutathionylation induces the dissociation of 1-Cys D-peroxiredoxin non-covalent homodimer.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 18084889
Journal Subcell Biochem
Year 2007
Volume 44
Pages 41-60
Authors Karplus PA, Hall A
Title Structural survey of the peroxiredoxins.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 19737009
Journal Biochemistry
Year 2009
Volume 48
Pages 9416-26
Authors Hugo M, Turell L, Manta B, Botti H, Monteiro G, Netto LE, Alvarez B, Radi R, Trujillo M
Title Thiol and sulfenic acid oxidation of AhpE, the one-cysteine peroxiredoxin from Mycobacterium tuberculosis: kinetics, acidity constants, and conformational dynamics.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 20969484
Journal Antioxid Redox Signal
Year 2011
Volume 15
Pages 795-815
Authors Hall A, Nelson K, Poole LB, Karplus PA
Title Structure-based insights into the catalytic power and conformational dexterity of peroxiredoxins.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 21571062
Journal Free Radic Biol Med
Year 2011
Volume 51
Pages 464-73
Authors Reyes AM, Hugo M, Trostchansky A, Capece L, Radi R, Trujillo M
Title Oxidizing substrate specificity of Mycobacterium tuberculosis alkyl hydroperoxide reductase E: kinetics and mechanisms of oxidation and overoxidation.
Related PDB
Related UniProtKB

Comments
Peroxiredoxins (Prxs) can be classified into three categories (see [2]):
(1) typical 2-Cys Prxs; conservation of two redox-active cysteines; homodimers having two identical active sites.
(2) atypical 2-Cys Prxs; conservation of two redox-active cysteines; functionally monomeric.
(3) 1-Cys Prxs; only one cysteine.
This enzyme belongs to the category of 1-Cys Prxs.
The redox-active cysteine is referred to as the peroxidatic cysteine, in contrast to the second cysteine, the resolving cysteine, in the 2-Cys Prxs.
Since this enzyme is homologous to two-domain peroxiredoxin (D00869 in EzCatDB), it must have a similar catalytic mechanism as the homologue.
Thus, this enzyme catalyzes the following reactions (see [2], [3], [4]):
(A) Transfer of peroxide oxygen from another peroxide oxygen to the perdoxidatic Cys, forming Cys-sulfenic acid:
(A0) Sidechains of Thr42 and Arg116 (of 1xxu) may lower the pKa of sidechain of Cys45, along with the mainchain amide groups of Leu39 and Cys45.
(A1) The thiolate of Cys45 makes a nucleophilic (in-line) attack on the electrophilic oxygen atom of hydroperoxide, leading to the transition-state (SN2-like reaction).
(A2) During the transition-state, sidechains of Arg116 and Thr42 stabilize the transferred oxygen atom, whereas the acceptor, thiolate of Cys45, is stabilized by sidechains of Arg116 and Thr42, and mainchain amide of Cys45. Moreover, the leaving alkoxide (RO-) is stabilized by mainchain amide of Ile44.
(A3) Finally, the bond cleavage and new bond formation complete.
(B) Transfer of sulfur atom of the peroxidatic Cys from the hydroxyl group to thiol (or sulfhydryl) group of the second substrate (R'-SH; Glutaredoxin or glutathione), releasing H2O and forming a disulfide bond:
(B1) Activated thiol makes a nucleophilic attack on the sulfur atom of Cys45, relasing OH group. This reaction forms a new disulfide bond between Cys45 and thiol of the second substrate. However, it is not clear how the thiol group can be activated for the nucleophilicity, and whether a protonation to leaving OH group occurs.
(C) Electron transfer from thiol of the third substrate (or another R'-SH) to the disulfide bond (thiol-disulfide exchange):
(C1) Thiol of another R'-SH makes a nucleophilic attack on the sulfur atom of sulfur atom (from the second substrate) of the disulfide bond, relasing Cys45. This reaction forms a new disulfide bond between the two substrates (R'-SH). However, it is not clear how the thiol can be activated for the nucleophilicity.
Although this enzyme can be over-oxidized to form sulfinic acid (-SO2H) and further oxidized sulfonic acid (-SO3H), over-oxidization mechanism is not described in this entry. Incidentally, 1xiy (of PDB) gives structures of sulfonic acid form.

Created Updated
2011-07-13 2012-09-11