EzCatDB: M00205
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DB codeM00205
CATH domainDomain 11.-.-.-
Domain 21.10.395.10
Domain 33.90.244.10Catalytic domain
Domain 43.90.188.10Catalytic domain
Domain 5-.-.-.-
Domain 61.10.620.20 : Ribonucleotide Reductase, subunit ACatalytic domain
E.C.1.17.4.1

CATH domainRelated DB codes (homologues)
1.10.620.20 : Ribonucleotide Reductase, subunit AS00028,M00151,M00204
3.90.188.10M00204
3.90.244.10M00204

Enzyme Name
UniProtKBKEGG

P21524P21672P09938P49723
Protein nameRibonucleoside-diphosphate reductase large chain 1Ribonucleoside-diphosphate reductase large chain 2Ribonucleoside-diphosphate reductase small chain 1Ribonucleoside-diphosphate reductase small chain 2ribonucleoside-diphosphate reductase
ribonucleotide reductase
CDP reductase
ribonucleoside diphosphate reductase
UDP reductase
ADP reductase
nucleoside diphosphate reductase
ribonucleoside 5'-diphosphate reductase
ribonucleotide diphosphate reductase
2'-deoxyribonucleoside-diphosphate:oxidized-thioredoxin2'-oxidoreductase
RR
SynonymsEC 1.17.4.1
Ribonucleotide reductase large subunit 1
Ribonucleotide reductase R1 subunit 1
EC 1.17.4.1
Ribonucleotide reductase large subunit 2
Ribonucleotide reductase DNA damage-inducible regulatory subunit 2
Ribonucleotide reductase R1 subunit 2
EC 1.17.4.1
Ribonucleotide reductase small subunit 1
Ribonucleotide reductase R2 subunit 1
EC 1.17.4.1
Ribonucleotide reductase small subunit 2
Ribonucleotide reductase R2 subunit 2
RefSeqNP_010993.1 (Protein)
NM_001178961.1 (DNA/RNA sequence)
NP_012198.3 (Protein)
NM_001179416.3 (DNA/RNA sequence)
NP_012508.1 (Protein)
NM_001181460.1 (DNA/RNA sequence)
NP_011696.3 (Protein)
NM_001181309.3 (DNA/RNA sequence)
PfamPF03477 (ATP-cone)
PF02867 (Ribonuc_red_lgC)
PF00317 (Ribonuc_red_lgN)
[Graphical view]
PF03477 (ATP-cone)
PF02867 (Ribonuc_red_lgC)
PF00317 (Ribonuc_red_lgN)
[Graphical view]
PF00268 (Ribonuc_red_sm)
[Graphical view]
PF00268 (Ribonuc_red_sm)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00230Purine metabolism
MAP00240Pyrimidine metabolism
MAP00480Glutathione metabolism

UniProtKB:Accession NumberP21524P21672P09938P49723
Entry nameRIR1_YEASTRIR3_YEASTRIR2_YEASTRIR4_YEAST
Activity2''-deoxyribonucleoside diphosphate + thioredoxin disulfide + H(2)O = ribonucleoside diphosphate + thioredoxin.2''-deoxyribonucleoside diphosphate + thioredoxin disulfide + H(2)O = ribonucleoside diphosphate + thioredoxin.2''-deoxyribonucleoside diphosphate + thioredoxin disulfide + H(2)O = ribonucleoside diphosphate + thioredoxin.2''-deoxyribonucleoside diphosphate + thioredoxin disulfide + H(2)O = ribonucleoside diphosphate + thioredoxin.
SubunitHeterotetramer of two large (R1) and two small (R2) subunits. S.cerevisiae has two different R1 subunits (RNR1 and RNR3) and two different R2 subunits (RNR2 and RNR4). The functional form of the small subunits is a RNR2-RNR4 heterodimer, where RNR2 provides the iron-radical center and RNR4 is required for proper folding of RNR2 and assembly with the large subunits. Under normal growth conditions, the active form of the large subunits is a homodimer of the constitutively expressed RNR1. In damaged cells or cells arrested for DNA synthesis, the reductase consists of multiple species because of the association of the small subunits (RNR2-RNR4) with either the RNR1 homodimer or a heterodimer of RNR1 and the damage-inducible RNR3. RNR1 interacts with the ribonucleotide reductase inhibitor SML1.Heterotetramer of two large (R1) and two small (R2) subunits. S.cerevisiae has two different R1 subunits (RNR1 and RNR3) and two different R2 subunits (RNR2 and RNR4). The functional form of the small subunits is a RNR2-RNR4 heterodimer, where RNR2 provides the iron-radical center and RNR4 is required for proper folding of RNR2 and assembly with the large subunits. Under normal growth conditions, the active form of the large subunits is a homodimer of the constitutively expressed RNR1. In damaged cells or cells arrested for DNA synthesis, the reductase consists of multiple species because of the association of the small subunits (RNR2-RNR4) with either the RNR1 homodimer or a heterodimer of RNR1 and the damage-inducible RNR3.Heterotetramer of two large (R1) and two small (R2) subunits. S.cerevisiae has two different R1 subunits (RNR1 and RNR3) and two different R2 subunits (RNR2 and RNR4). The functional form of the small subunits is a RNR2-RNR4 heterodimer, where RNR2 provides the iron-radical center and RNR4 is required for proper folding of RNR2 and assembly with the large subunits. Under normal growth conditions, the active form of the large subunits is a homodimer of the constitutively expressed RNR1. In damaged cells or cells arrested for DNA synthesis, the reductase consists of multiple species because of the association of the small subunits (RNR2-RNR4) with either the RNR1 homodimer or a heterodimer of RNR1 and the damage-inducible RNR3.Heterotetramer of two large (R1) and two small (R2) subunits. S.cerevisiae has two different R1 subunits (RNR1 and RNR3) and two different R2 subunits (RNR2 and RNR4). The functional form of the small subunits is a RNR2-RNR4 heterodimer, where RNR2 provides the iron-radical center and RNR4 is required for proper folding of RNR2 and assembly with the large subunits. Under normal growth conditions, the active form of the large subunits is a homodimer of the constitutively expressed RNR1. In damaged cells or cells arrested for DNA synthesis, the reductase consists of multiple species because of the association of the small subunits (RNR2-RNR4) with either the RNR1 homodimer or a heterodimer of RNR1 and the damage-inducible RNR3.
Subcellular locationCytoplasm.Cytoplasm.Nucleus. Note=Found predominantly in the nucleus under normal growth conditions and is redistributed to the cytoplasm in damaged cells in a DNA replication and damage checkpoint-dependent manner.Nucleus. Note=Found predominantly in the nucleus under normal growth conditions and is redistributed to the cytoplasm in damaged cells in a DNA replication and damage checkpoint-dependent manner.
Cofactor

Binds 2 iron ions per subunit.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00023C00002C00342C03723C04232C00343C00001
CompoundIronATPReduced thioredoxinRibonucleoside diphosphate2'-Deoxyribonucleoside diphosphateOxidized thioredoxinH2O
Typeheavy metalamine group,nucleotideamide group,carbohydrate,peptide/protein,sulfhydryl groupnucleotidenucleotideamide group,carbohydrate,disulfide bond,peptide/proteinH2O
ChEBI18248
82664
15422




15377
PubChem23925
5957




962
22247451
               
1zyzA01UnboundUnboundUnboundUnboundUnboundUnbound 
1zyzB01UnboundUnboundUnboundUnboundUnboundUnbound 
2cvsA01UnboundUnboundUnboundUnboundUnboundUnbound 
2cvtA01UnboundUnboundUnboundUnboundUnboundUnbound 
2cvxA01UnboundUnboundUnboundUnboundUnboundUnbound 
1zyzA02UnboundUnboundUnboundUnboundUnboundUnbound 
1zyzB02UnboundUnboundUnboundUnboundUnboundUnbound 
1zzdA01UnboundUnboundUnboundUnboundUnboundUnbound 
2cvsA02UnboundUnboundUnboundUnboundUnboundUnbound 
2cvtA02UnboundUnboundUnboundUnboundUnboundUnbound 
2cvuA01UnboundUnboundUnboundUnboundUnboundUnbound 
2cvvA01UnboundUnboundUnboundUnboundUnboundUnbound 
2cvwA01UnboundUnboundUnboundUnboundUnboundUnbound 
2cvxA02UnboundUnboundUnboundUnboundUnboundUnbound 
2cvyA01UnboundUnboundUnboundUnboundUnboundUnbound 
2eudA01UnboundUnboundUnboundUnboundUnboundUnbound 
1zyzA03UnboundUnboundUnboundUnboundUnboundUnbound 
1zyzB03UnboundUnboundUnboundUnboundUnboundUnbound 
1zzdA02UnboundUnboundUnboundUnboundUnboundUnbound 
2cvsA03UnboundUnboundUnboundUnboundUnboundUnbound 
2cvtA03UnboundUnboundUnboundUnboundUnboundUnbound 
2cvuA02UnboundUnboundUnboundBound:CDPUnboundUnbound 
2cvvA02UnboundUnboundUnboundBound:UDPUnboundUnbound 
2cvwA02UnboundUnboundUnboundBound:GDPUnboundUnbound 
2cvxA03UnboundUnboundUnboundBound:ADPUnboundUnbound 
2cvyA02UnboundUnboundUnboundUnboundUnboundUnbound 
2eudA02UnboundUnboundUnboundAnalogue:GCQUnboundUnbound 
1zyzA04UnboundUnboundUnboundUnboundUnboundUnbound 
1zyzB04UnboundUnboundUnboundUnboundUnboundUnbound 
1zzdA03UnboundUnboundUnboundUnboundUnboundUnbound 
2cvsA04UnboundUnboundUnboundUnboundUnboundUnbound 
2cvtA04UnboundAnalogue:ANPUnboundUnboundUnboundUnbound 
2cvuA03UnboundAnalogue:ANPUnboundUnboundUnboundUnbound 
2cvvA03UnboundAnalogue:ANPUnboundUnboundUnboundUnbound 
2cvwA03UnboundAnalogue:TTPUnboundUnboundUnboundUnbound 
2cvxA04UnboundAnalogue:DGTUnboundUnboundUnboundUnbound 
2cvyA03UnboundAnalogue:TTPUnboundUnboundUnboundUnbound 
2eudA03UnboundAnalogue:ANPUnboundUnboundUnboundUnbound 
1jk0AAnalogue:_ZNUnboundUnboundUnboundUnboundUnbound 
1smqAUnboundUnboundUnboundUnboundUnboundUnbound 
1smqBUnboundUnboundUnboundUnboundUnboundUnbound 
1smqCUnboundUnboundUnboundUnboundUnboundUnbound 
1smqDUnboundUnboundUnboundUnboundUnboundUnbound 
1jk0BUnboundUnboundUnboundUnboundUnboundUnbound 
1smsAUnboundUnboundUnboundUnboundUnboundUnbound 
1smsBUnboundUnboundUnboundUnboundUnboundUnbound 

Active-site residues
resource
PDB;2r1r, 3r1r & Swiss-prot;P00452 & literature [14]
pdbCatalytic residuesCofactor-binding residuescomment
           
1zyzA01 
 
 
1zyzB01 
 
 
2cvsA01 
 
 
2cvtA01 
 
 
2cvxA01 
 
 
1zyzA02 
 
 
1zyzB02 
 
 
1zzdA01 
 
 
2cvsA02 
 
 
2cvtA02 
 
 
2cvuA01 
 
 
2cvvA01 
 
 
2cvwA01 
 
 
2cvxA02 
 
 
2cvyA01 
 
 
2eudA01 
 
 
1zyzA03TYR 741;TYR 742
 
 
1zyzB03TYR 741;TYR 742
 
 
1zzdA02TYR 741;TYR 742
 
 
2cvsA03TYR 741;TYR 742
 
 
2cvtA03TYR 741;TYR 742
 
 
2cvuA02TYR 741;TYR 742
 
 
2cvvA02TYR 741;TYR 742
 
 
2cvwA02TYR 741;TYR 742
 
 
2cvxA03TYR 741;TYR 742
 
 
2cvyA02TYR 741;TYR 742
 
 
2eudA02TYR 741;TYR 742
 
 
1zyzA04CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
1zyzB04CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
1zzdA03CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
disulfide bonded/oxidized form C218-C443
2cvsA04CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
disulfide bonded/oxidized form C218-C443
2cvtA04CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
2cvuA03CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
2cvvA03CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
2cvwA03CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
2cvxA04CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
2cvyA03CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
disulfide bonded/oxidized form C218-C443
2eudA03CYS 218;ASN 426;CYS 428;GLU 430;CYS 443
 
 
1jk0ATYR 183
ASP 145;HIS 179(Iron-1);GLU 239;HIS 276(Iron-2);GLU 176;GLU 273(both Iron-1 & Iron-2)
 
1smqATYR 183
       ;HIS 179(Iron-1);GLU 239;HIS 276(Iron-2);GLU 176;GLU 273(both Iron-1 & Iron-2)
invisible 145-149
1smqBTYR 183
       ;HIS 179(Iron-1);GLU 239;HIS 276(Iron-2);GLU 176;GLU 273(both Iron-1 & Iron-2)
invisible 145-149
1smqCTYR 183
       ;HIS 179(Iron-1);GLU 239;HIS 276(Iron-2);GLU 176;GLU 273(both Iron-1 & Iron-2)
invisible 145-149
1smqDTYR 183
       ;HIS 179(Iron-1);GLU 239;HIS 276(Iron-2);GLU 176;GLU 273(both Iron-1 & Iron-2)
invisible 145-149
1jk0BTYR 131
 
 
1smsATYR 131
 
 
1smsBTYR 131
 
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[3]Scheme I, p.12750
[3]Scheme II, p.12750
[3]Scheme III, p.12751
[7]FIG. 4c, p.537
[9]Scheme 1, p.8382
[9]Scheme 2, p.8389
[9]Scheme 3, p.8389
[9]Scheme 4, p.8389
[10]FScheme 2, p.10066
[13]FIG. 2, p.31534
[14]Figure 9, p.1088
[23]SCHEME 1, p.60
[25]SCHEME 1, p.5750
[25]SCHEME 2, p.5752
[26]Figure 3, p.313
[26]Figure 4, p.314
[26]Figure 7, p.316

references
[1]
CommentsSubunit R2
PubMed ID1963165
JournalFree Radic Res Commun
Year1990
Volume10
Pages281-6
AuthorsHarder J, Follmann H
TitleIdentification of a free radical and oxygen dependence of ribonucleotide reductase in yeast.
[2]
CommentsSubunit R1
PubMed ID11074005
JournalMol Cell Biol
Year2000
Volume20
Pages9076-83
AuthorsZhao X, Georgieva B, Chabes A, Domkin V, Ippel JH, Schleucher J, Wijmenga S, Thelander L, Rothstein R
TitleMutational and structural analyses of the ribonucleotide reductase inhibitor Sml1 define its Rnr1 interaction domain whose inactivation allows suppression of mec1 and rad53 lethality.
[3]
CommentsSubunit R2
PubMed ID11472128
JournalJ Am Chem Soc
Year2001
Volume123
Pages3569-76
AuthorsBar G, Bennati M, Nguyen HH, Ge J, Stubbe JA, Griffin RG
TitleHigh-frequency (140-GHz) time domain EPR and ENDOR spectroscopy: the tyrosyl radical-diiron cofactor in ribonucleotide reductase from yeast.
[4]
CommentsX-ray crystallography, Subunit R2
PubMed ID11526233
JournalProc Natl Acad Sci U S A
Year2001
Volume98
Pages10073-8
AuthorsVoegtli WC, Ge J, Perlstein DL, Stubbe J, Rosenzweig AC
TitleStructure of the yeast ribonucleotide reductase Y2Y4 heterodimer.
Related PDB1jk0
[5]
CommentsX-ray crystallography, Subunit R2
PubMed ID15196016
JournalBiochemistry
Year2004
Volume43
Pages7736-42
AuthorsSommerhalter M, Voegtli WC, Perlstein DL, Ge J, Stubbe J, Rosenzweig AC
TitleStructures of the yeast ribonucleotide reductase Rnr2 and Rnr4 homodimers.
Related PDB1smq,1sms
[6]
CommentsSubunit R1
PubMed ID16537479
JournalProc Natl Acad Sci U S A
Year2006
Volume103
Pages4022-7
AuthorsXu H, Faber C, Uchiki T, Fairman JW, Racca J, Dealwis C
TitleStructures of eukaryotic ribonucleotide reductase I provide insights into dNTP regulation.
Related PDB1zyz,1zzd,2cvs,2cvt,2cvu,2cvv,2cvw,2cvx,2cvy
[7]
CommentsSubunit R1
PubMed ID16537480
JournalProc Natl Acad Sci U S A
Year2006
Volume103
Pages4028-33
AuthorsXu H, Faber C, Uchiki T, Racca J, Dealwis C
TitleStructures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly.
Related PDB2eud

comments
This enzyme belongs to the class I ribonucleotide reductases (RNR). The class I enzyme can be further subdivided into Ia and Ib. This entry is for the subclass Ia, whose subunits are large subunits (R1) and small ones (R2). Moreover, Unlike the other homologous counterpart enzyme, both the subunits have got two different subunits, RNR1 and RNR3 for the large one, and RNR2 and RNR4 for the large one.
The functional form of the small subunits is a RNR2-RNR4 heterodimer, in which RNR2 gives active site for radical generation with cofactor di-iron bound, and RNR4 supports the folding of the RNR2 subunit (see [4]).
Futhermore, this enzyme has different domains, from other counterpart enzymes, at the N-terminus and C-terminus. The tertiary structure of the C-terminal domain, which is an additional domain, has not been determined yet.
The class Ia enzyme has got a allosteric regulation by ATP.
According to the counterpart enzyme from Salmonella typhimurium (M00204 in EzCatDB), this enzyme catalyzes the following reactions:
(A) Electron transfer from thioredoxin (an external donor) to the redox-active Cys883-Cys886 of RNR1 (or Cys864-Cys867 of RNR3) (disulfide) at the C-terminus of the R1 subunit.
(B) Electron transfer from the C-terminus redox-active cysteine pair to the active site redox-active Cys218-Cys443.
(C) Electron transfer from the active site redox-active cysteine pair (Cys218 & Cys443) to the substrate nucleotide.
(D) Radical formation at Tyr183 of the R2 subunit (RNR2):
(E) Radical transfer from Tyr183 to the di-iron site of the R2 subunit (RNR2).
(F) Radical transfer from the di-iron site to the active site Cys428, through Tyr741/Tyr742 of the R1 subunit, generating a thiyl radical at Cys428.
(G) Radical reaction for the substrate nucleotide at the active site Cys428.
#####
Other classes are as follows:
Class I enzymes: M00011 (class Ia), M00204 (class Ib)
Clsss II enzyme (e.g. adenocylcobalamine-dependent rebonucleotide reductase from Lactobacillus leichmannii, E.C 1.17.4.2).
Class III enzyme (E.C. 1.17.4.2): M00203

createdupdated
2004-03-252009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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