EzCatDB: S00916
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DB codeS00916
RLCP classification3.676.249900.37 : Transfer
CATH domainDomain 13.40.30.10 : GlutaredoxinCatalytic domain
E.C.1.11.1.15

CATH domainRelated DB codes (homologues)
3.40.30.10 : GlutaredoxinS00279,M00184,D00866,D00869,D00870,D00278

Enzyme Name
UniProtKBKEGG

P65688Q5MYR6Q8S3L0
Protein namePutative peroxiredoxin Rv2238c/MT2298

Peroxiredoxin
Thioredoxin peroxidase
Tryparedoxin peroxidase
Alkyl hydroperoxide reductase C22
AhpC
TrxPx
TXNPx
Prx
PRDX
SynonymsEC 1.11.1.15
Thioredoxin reductase
Peroxiredoxin
Peroxiredoxin
RefSeqNP_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)
XP_002808799.1 (Protein)
XM_002808753.1 (DNA/RNA sequence)

PfamPF00578 (AhpC-TSA)
[Graphical view]
PF08534 (Redoxin)
[Graphical view]
PF08534 (Redoxin)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00480Glutathione metabolism

UniProtKB:Accession NumberP65688Q5MYR6Q8S3L0
Entry nameY2238_MYCTUQ5MYR6_PLAF7Q8S3L0_9ROSI
Activity2 R'-SH + ROOH = R'-S-S-R' + H2O + ROH.

Subunit


Subcellular location


Cofactor



Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC16736C15498C15496C00001C01335I00142I00143
CompoundR'-SHROOHR'-S-S-R'H2OROHPeptidyl-Cys-sulfenic acidTransient disulfide bond between peptidyl-Cys
Typesulfhydryl groupothersdisulfide bondH2Ocarbohydrate

ChEBI


15377



PubChem


962
22247451



               
1xvwAUnboundUnboundUnbound UnboundIntermediate-bound:CSOUnbound
1xvwBUnboundUnboundUnbound UnboundIntermediate-bound:CSOUnbound
1xxuA00UnboundUnboundUnbound UnboundUnboundUnbound
1xxuB00UnboundUnboundUnbound UnboundUnboundUnbound
1xxuC00UnboundUnboundUnbound UnboundUnboundUnbound
1xxuD00UnboundUnboundUnbound UnboundUnboundUnbound
1xiyAUnboundUnboundUnbound UnboundIntermediate-analogue:OCSUnbound
1xiyBUnboundUnboundUnbound UnboundIntermediate-analogue:OCSUnbound
1tp9A00UnboundUnboundUnbound UnboundUnboundUnbound
1tp9B00UnboundUnboundUnbound UnboundUnboundUnbound
1tp9C00UnboundUnboundUnbound UnboundUnboundUnbound
1tp9D00UnboundUnboundUnbound UnboundUnboundUnbound

Active-site residues
resource
Literature [4], [5], [6], [7], [9]
pdbCatalytic residuesModified residuesMain-chain involved in catalysis
           
1xvwATHR 42;      ;ARG 116
CSO 45(S-hydroxycysteine)    
LEU 39;ILE 44;CSO 45
1xvwBTHR 42;      ;ARG 116
CSO 45(S-hydroxycysteine)    
LEU 39;ILE 44;CSO 45
1xxuA00THR 42;CYS 45;ARG 116
                             
LEU 39;ILE 44;CYS 45
1xxuB00THR 42;CYS 45;ARG 116
                             
LEU 39;ILE 44;CYS 45
1xxuC00THR 42;CYS 45;ARG 116
                             
LEU 39;ILE 44;CYS 45
1xxuD00THR 42;CYS 45;ARG 116
                             
LEU 39;ILE 44;CYS 45
1xiyATHR 56;      ;ARG 137
OCS 59(Cysteinesulfonic acid)
GLY 53;THR 58;OCS 59
1xiyBTHR 56;      ;ARG 137
OCS 59(Cysteinesulfonic acid)
GLY 53;THR 58;OCS 59
1tp9A00THR 48;CYS 51;ARG 129
                             
GLY 45;THR 50;CYS 51
1tp9B00THR 48;CYS 51;ARG 129
                             
GLY 45;THR 50;CYS 51
1tp9C00THR 48;CYS 51;ARG 129
                             
GLY 45;THR 50;CYS 51
1tp9D00THR 48;CYS 51;ARG 129
                             
GLY 45;THR 50;CYS 51

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]Fig. 4
[2]Fig. 1
[6]FIGURE 5

references
[1]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
PubMed ID9587003
JournalNat Struct Biol
Year1998
Volume5
Pages400-6
AuthorsChoi HJ, Kang SW, Yang CH, Rhee SG, Ryu SE
TitleCrystal structure of a novel human peroxidase enzyme at 2.0 A resolution.
Related PDB1prx
Related UniProtKBP30041
[2]
PubMed ID12517450
JournalTrends Biochem Sci
Year2003
Volume28
Pages32-40
AuthorsWood ZA, Schroder E, Robin Harris J, Poole LB
TitleStructure, mechanism and regulation of peroxiredoxins.
[3]
PubMed ID15697201
JournalBiochemistry
Year2005
Volume44
Pages1755-67
AuthorsEchalier A, Trivelli X, Corbier C, Rouhier N, Walker O, Tsan P, Jacquot JP, Aubry A, Krimm I, Lancelin JM
TitleCrystal structure and solution NMR dynamics of a D (type II) peroxiredoxin glutaredoxin and thioredoxin dependent: a new insight into the peroxiredoxin oligomerism.
Related PDB1tp9
Related UniProtKBQ8S3L0
[4]
PubMed ID15701515
JournalJ Mol Biol
Year2005
Volume346
Pages1035-46
AuthorsLi S, Peterson NA, Kim MY, Kim CY, Hung LW, Yu M, Lekin T, Segelke BW, Lott JS, Baker EN
TitleCrystal Structure of AhpE from Mycobacterium tuberculosis, a 1-Cys peroxiredoxin.
Related PDB1xvw,1xxu
Related UniProtKBP65688
[5]
PubMed ID15701514
JournalJ Mol Biol
Year2005
Volume346
Pages1021-34
AuthorsSarma GN, Nickel C, Rahlfs S, Fischer M, Becker K, Karplus PA
TitleCrystal structure of a novel Plasmodium falciparum 1-Cys peroxiredoxin.
Related PDB1xiy
Related UniProtKBQ5MYR6
[6]
PubMed ID16916801
JournalJ Biol Chem
Year2006
Volume281
Pages31736-42
AuthorsNoguera-Mazon V, Lemoine J, Walker O, Rouhier N, Salvador A, Jacquot JP, Lancelin JM, Krimm I
TitleGlutathionylation induces the dissociation of 1-Cys D-peroxiredoxin non-covalent homodimer.
[7]
PubMed ID18084889
JournalSubcell Biochem
Year2007
Volume44
Pages41-60
AuthorsKarplus PA, Hall A
TitleStructural survey of the peroxiredoxins.
[8]
PubMed ID19737009
JournalBiochemistry
Year2009
Volume48
Pages9416-26
AuthorsHugo M, Turell L, Manta B, Botti H, Monteiro G, Netto LE, Alvarez B, Radi R, Trujillo M
TitleThiol and sulfenic acid oxidation of AhpE, the one-cysteine peroxiredoxin from Mycobacterium tuberculosis: kinetics, acidity constants, and conformational dynamics.
[9]
PubMed ID20969484
JournalAntioxid Redox Signal
Year2011
Volume15
Pages795-815
AuthorsHall A, Nelson K, Poole LB, Karplus PA
TitleStructure-based insights into the catalytic power and conformational dexterity of peroxiredoxins.
[10]
PubMed ID21571062
JournalFree Radic Biol Med
Year2011
Volume51
Pages464-73
AuthorsReyes AM, Hugo M, Trostchansky A, Capece L, Radi R, Trujillo M
TitleOxidizing substrate specificity of Mycobacterium tuberculosis alkyl hydroperoxide reductase E: kinetics and mechanisms of oxidation and overoxidation.

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.

createdupdated
2011-07-132012-09-11


Copyright: Nozomi Nagano, JST & CBRC-AIST
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Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
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Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
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