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
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 15377
PubChem				22247451 962 22247451 962

1xvwA	Unbound	Unbound	Unbound		Unbound	Intermediate-bound:CSO	Unbound
1xvwB	Unbound	Unbound	Unbound		Unbound	Intermediate-bound:CSO	Unbound
1xxuA00	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1xxuB00	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1xxuC00	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1xxuD00	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1xiyA	Unbound	Unbound	Unbound		Unbound	Intermediate-analogue:OCS	Unbound
1xiyB	Unbound	Unbound	Unbound		Unbound	Intermediate-analogue:OCS	Unbound
1tp9A00	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1tp9B00	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1tp9C00	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1tp9D00	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	THR 42; ;ARG 116		CSO 45(S-hydroxycysteine)	LEU 39;ILE 44;CSO 45
1xvwB	THR 42; ;ARG 116		CSO 45(S-hydroxycysteine)	LEU 39;ILE 44;CSO 45
1xxuA00	THR 42;CYS 45;ARG 116			LEU 39;ILE 44;CYS 45
1xxuB00	THR 42;CYS 45;ARG 116			LEU 39;ILE 44;CYS 45
1xxuC00	THR 42;CYS 45;ARG 116			LEU 39;ILE 44;CYS 45
1xxuD00	THR 42;CYS 45;ARG 116			LEU 39;ILE 44;CYS 45
1xiyA	THR 56; ;ARG 137		OCS 59(Cysteinesulfonic acid)	GLY 53;THR 58;OCS 59
1xiyB	THR 56; ;ARG 137		OCS 59(Cysteinesulfonic acid)	GLY 53;THR 58;OCS 59
1tp9A00	THR 48;CYS 51;ARG 129			GLY 45;THR 50;CYS 51
1tp9B00	THR 48;CYS 51;ARG 129			GLY 45;THR 50;CYS 51
1tp9C00	THR 48;CYS 51;ARG 129			GLY 45;THR 50;CYS 51
1tp9D00	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.

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