DB code: D00869

RLCP classification	3.676.249900.37 : Transfer
CATH domain	3.40.30.10 : Glutaredoxin	Catalytic domain
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	S00916 S00279 M00184 D00866 D00870 D00278

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	Pfam
P44758	Hybrid peroxiredoxin hyPrx5	EC 1.11.1.15 Thioredoxin reductase	NP_438729.1 (Protein) NC_000907.1 (DNA/RNA sequence)	PF00462 (Glutaredoxin) 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
P44758	PRX5_HAEIN	2 R'-SH + ROOH = R'-S-S-R' + H(2)O + ROH.	Homotetramer.

KEGG Pathways
Map code	Pathways	E.C.

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

1nm3A01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1nm3B01	Unbound	Unbound	Unbound		Unbound	Unbound	Unbound
1nm3A02	Unbound	Unbound	Bound:CYS_180-CYS_183		Unbound	Unbound	Unbound
1nm3B02	Unbound	Unbound	Bound:CYS_180-CYS_183		Unbound	Unbound	Unbound

Reference for Active-site residues
resource	references	E.C.
Literature [1], [2], [3], [4], [6], [7]

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

1nm3A01	THR 46;CYS 49;ARG 126			GLY 43;THR 48;CYS 49
1nm3B01	THR 46;CYS 49;ARG 126			GLY 43;THR 48;CYS 49
1nm3A02	CYS 180;CYS 183
1nm3B02	CYS 180;CYS 183

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[2]	Fig. 1
[4]	Figure 2, Figure 3
[5]	Fig. 7
[6]	Fig. 8
[8]	Scheme 2

References
[1]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
Medline ID
PubMed ID	12529327
Journal	J Biol Chem
Year	2003
Volume	278
Pages	10790-8
Authors	Kim SJ, Woo JR, Hwang YS, Jeong DG, Shin DH, Kim K, Ryu SE
Title	The tetrameric structure of Haemophilus influenza hybrid Prx5 reveals interactions between electron donor and acceptor proteins.
Related PDB	1nm3
Related UniProtKB	P44758
[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	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
[4]
Resource
Comments
Medline ID
PubMed ID	18084890
Journal	Subcell Biochem
Year	2007
Volume	44
Pages	61-81
Authors	Poole LB
Title	The catalytic mechanism of peroxiredoxins.
Related PDB
Related UniProtKB
[5]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (1.47 ANGSTROMS).
Medline ID
PubMed ID	19477183
Journal	J Mol Biol
Year	2009
Volume	390
Pages	951-66
Authors	Liao SJ, Yang CY, Chin KH, Wang AH, Chou SH
Title	Insights into the alkyl peroxide reduction pathway of Xanthomonas campestris bacterioferritin comigratory protein from the trapped intermediate-ligand complex structures.
Related PDB	3gkk 3gkm 3gkn
Related UniProtKB	Q8P9V9
[6]
Resource
Comments
Medline ID
PubMed ID	20643143
Journal	J Mol Biol
Year	2010
Volume	402
Pages	194-209
Authors	Hall A, Parsonage D, Poole LB, Karplus PA
Title	Structural evidence that peroxiredoxin catalytic power is based on transition-state stabilization.
Related PDB	3mng
Related UniProtKB	P30044
[7]
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
[8]
Resource
Comments
Medline ID
PubMed ID	21391663
Journal	Chem Res Toxicol
Year	2011
Volume	24
Pages	434-50
Authors	Ferrer-Sueta G, Manta B, Botti H, Radi R, Trujillo M, Denicola A
Title	Factors affecting protein thiol reactivity and specificity in peroxide reduction.
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. Moreover, this enzyme has a glutaredoxin (Grx) domain in the C-terminus, which contains two cysteine residues (Cys180 and Cys 183) that can act as an electron donor for the Prx domain. According to the literature [1], oxidized C-terminal Grx domain can be reduced by reduced glutathione (GSH). Cys180 can form a disulfide bond with the cysteine residue of GSH. Thus, this enzyme catalyzes the following reactions (see [1], [2], [6], [8]): (A) Transfer of peroxide oxygen from another peroxide oxygen to the peroxidatic Cys, forming Cys-sulfenate (I00142): (A0) Sidechains of Thr46 and Arg126 may lower the pKa of sidechain of Cys49, along with the mainchain amide groups of Gly43 and Cys49. (A1) The thiolate of Cys49 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 Arg126 and Thr46 stabilize the transferred oxygen atom, whereas the acceptor, thiolate of Cys49, is stabilized by sidechains of Arg126 and Thr46, and mainchain amide of Cys49. Moreover, the leaving alkoxide (RO-) is stabilized by mainchain amide of Thr48. (A3) Finally, the bond cleavage and new bond formation complete, forming an sulfenic acid intermediate (I00142). (B) Transfer of sulfur atom of the peroxidatic Cys from the hydroxyl group to Cys180 of Grx domain, releasing H2O and forming a disulfide bond (I00143): (B1) Cys180 makes a nucleophilic attack on the sulfur atom of Cys49, relasing OH group. This reaction forms a new disulfide bond between Cys49 and Cys180. However, it is not clear how Cys180 can be activated for the nucleophilicity, and whether a protonation to leaving OH group occurs. (C) Electron transfer from Cys183 of Grx domain to the disulfide bond (thiol-disulfide exchange): (C1) Cys183 makes a nucleophilic attack on the sulfur atom of Cys180, relasing Cys49. This reaction forms a new disulfide bond between Cys180 and Cys183. However, it is not clear how Cys183 can be activated for the nucleophilicity.

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.
Moreover, this enzyme has a glutaredoxin (Grx) domain in the C-terminus, which contains two cysteine residues (Cys180 and Cys 183) that can act as an electron donor for the Prx domain.
According to the literature [1], oxidized C-terminal Grx domain can be reduced by reduced glutathione (GSH). Cys180 can form a disulfide bond with the cysteine residue of GSH.
Thus, this enzyme catalyzes the following reactions (see [1], [2], [6], [8]):
(A) Transfer of peroxide oxygen from another peroxide oxygen to the peroxidatic Cys, forming Cys-sulfenate (I00142):
(A0) Sidechains of Thr46 and Arg126 may lower the pKa of sidechain of Cys49, along with the mainchain amide groups of Gly43 and Cys49.
(A1) The thiolate of Cys49 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 Arg126 and Thr46 stabilize the transferred oxygen atom, whereas the acceptor, thiolate of Cys49, is stabilized by sidechains of Arg126 and Thr46, and mainchain amide of Cys49. Moreover, the leaving alkoxide (RO-) is stabilized by mainchain amide of Thr48.
(A3) Finally, the bond cleavage and new bond formation complete, forming an sulfenic acid intermediate (I00142).
(B) Transfer of sulfur atom of the peroxidatic Cys from the hydroxyl group to Cys180 of Grx domain, releasing H2O and forming a disulfide bond (I00143):
(B1) Cys180 makes a nucleophilic attack on the sulfur atom of Cys49, relasing OH group. This reaction forms a new disulfide bond between Cys49 and Cys180. However, it is not clear how Cys180 can be activated for the nucleophilicity, and whether a protonation to leaving OH group occurs.
(C) Electron transfer from Cys183 of Grx domain to the disulfide bond (thiol-disulfide exchange):
(C1) Cys183 makes a nucleophilic attack on the sulfur atom of Cys180, relasing Cys49. This reaction forms a new disulfide bond between Cys180 and Cys183. However, it is not clear how Cys183 can be activated for the nucleophilicity.

Created	Updated
2012-07-17	2012-09-07