Ribonucleotide reductase

Function

Ribonucleotide reductase (RNR) or ribonucleotide-diphosphate reductase catalyzes the formation of deoxyribonucleotides from ribonucleotides^[1]. There are 3 classes of RNR.

Class Ia RNR is a tetramer composed from large (RNR1) and small (RNR2) subunits. Class I RNR is iron-dependent and produces tyrosyl radical. Thimidine triphosphate (TTP) is an effector in the reaction^[2].
Class Ib RNR contains 2 proteins: α (NrdE) and β (NrdF)^[3].

E. Coli contains two types of RNR: the aerobic RNR belongs to class Ia and is composed of proteins R1 and R2, the anaerobic RNR belongs to class Ib.

Class II RNR reduces ribonucleotide triphosphates using coenzyme B12^[4].
Class III RNR generate glycine radical using S-adenosyl methionine and Fe-S center^[5].

For details on human RNR2 see P53R2.

For mouse RNR see Mouse Ribonucleotide Reductase R2.
For RNR small subunit with nitrotyrosine modification see Nitrotyrosine.

Relevance

RNR inhibitors are studied as therapeutic antiviral, antibacterial and anti-cancer drugs^[6].

Structural highlights

Class II RNR is . The active site which binds the substrate is in a tight pocket and contains conserved residues involved in the catalytic mechanism ^[7].

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Class II ribonucleotide reductase dimer complex with dATP, UDP and Mg+2 ion (green) (PDB entry 1xjg)

Drag the structure with the mouse to rotate

3D Structures of Ribonucleotide reductase3D Structures of Ribonucleotide reductase

Updated on 16-October-2018

Class I ribonucleotide reductase
Ribonucleotide reductase large subunit
- 1zyz, 1zzd, 2cvs, 2cvt, 2cvu, 2cvv, 2cvw, 2cvx, 2cvy - yRNR R1 – yeast
- 1r1r - EcRNR R1 – Escherichia coli
- 1mrr - EcRNR R1 + Mn
- 5r1r, 6r1r, 7r1r, 1r1r – EcRNR R1 (mutant) + R2
Ribonucleotide reductase large subunit complex
- 3hnc – hRNR M1 + TTP – human
- 3hnd – hRNR M1 + GDP + TTP
- 3hne, 3hnf – hRNR M1 + ATP + TTP
- 2wgh, 5d1y - hRNR M1 + ATP + Mg
- 6aui - hRNR M1 + ATP + CDP
- 5tus, 4x3v - hRNR M1 + inhibitor + TTP
- 3paw - yRNR R1 + ATP
- 3k8t - yRNR R1 + ADP analog
- 3s87 - yRNR R1 + ADP + GTP
- 3s8a - yRNR R1 (mutant) + GTP
- 3tba - yRNR R1 (mutant) + GTP + ADP
- 3s8b - yRNR R1 + AMPPNP + CDP
- 3s8c, 3tb9 - yRNR R1 (mutant) + AMPPNP + CDP
- 2zlf, 2zlg - yRNR R1 + peptide
- 2eud - yRNR R1 + ligand
- 3rsr – yRNR R1 + inhibitor
- 1qfn - EcRNR R1 + glutaredoxin 1
RNR small subunit
- 2xof, 1av8, 1rib – EcRNR R2 + Fe2O
- 2alx, 1jqc, 1jpr - EcRNR R2 + Mn
- 1piy, 1r65, 1mxr, 1xik - EcRNR R2 + Fe
- 1piz, 1pj0, 1pj1, 1pim, 1piu, 1biq, 1pfr - EcRNR R2 (mutant) + Fe
- 1yfd, 2av8 - EcRNR R2 (mutant) + Fe2O
- 1pm2 - EcRNR R2 (mutant) + Mn
- 3hf1, 2vux, 2uw2, 4djn – hRNR M2
- 2p1i – RNR R2 – Plasmodium yoelii
- 2o1z - RNR R2 – Plasmodium vivax
- 1w68, 1h0n, 1h0o, 1xsm – mRNR R2 – mouse
- 1smq, 1sms – yRNR 2
- 4d8f, 4d8g, 4m1i - CtRNR R2 + Fe + Mn
- 1syy - CtRNR R2 + Fe + Pb– Chlamydia trachomatis
- 2ani - CtRNR R2 (mutant) + Fe + Pb
- 4m1h - CtRNR R2
- 1uzr – RNR R2 – Mycobacterium tuberculosis
- 3olj – hRNR M2
- 1jk0 – yRNR Y2+Y4
- 3vpm, 3vpn, 3vpo – hRNR M2 (mutant)
- 2rcc – RNR – Bacillus halodurans
- 4n83 - SsRNR + Mn
- 4hr5 - GkRNR – Geobacillus kaustophilus
- 5omj, 5omk - GkRNR + Fe
- 4hr0, 4hr4 - GkRNR + Fe + Mn
- 6f6c, 6f6e, 6f6f, 6f6g, 6f6h, 6f6k - GkRNR (mutant) + Fe + Mn
- 6cwo, 6cwq - FjRNR + Mn – Flavobacterium johnsoniae
Ribonucleotide reductase small subunit complex
- 1rsr, 1rsv - EcRNR R2 (mutant) + Fe + N3
- 1rnr – EcRNR R2 (mutant) + Fe + dopa
- 5ci4 – EcRNR R2 (mutant) + Fe2O
- 5ci3, 5ci0, 5ci1, 5ci2 – EcRNR R2 (mutant) + fluoro-tyrosine + Fe₂O
- 1w69 – mRNR R2 + acetate
- 6cwp – FjRNR + Mn + peptide
Ribonucleotide reductase small+large subunit
- 3uus - EcRNR R1+ R2 + Fe + ATP
- 4erm - EcRNR R1+ R2 + Fe2O + ATP + ADP
- 4erp - EcRNR R1+ R2 + Fe2O + ATP
- 2xak, 2xap, 2xo4, 2xo5 - EcRNR R1 modified+ R2 peptide
- 2xav, 2xaw, 2xax, 2xay, 2xaz, 2x0x - EcRNR R1 (mutant) modified + R2 peptide
- 5cns, 5cnt, 5cnv, 5cnu - EcRNR R1 + R2 + Fe2O + 2 nucleotides
- 2r1r - EcRNR R1 + R2 + TTP
- 3r1r - EcRNR R1 + R2 + AMPPNP
- 4r1r - EcRNR R1 + R2 + GDP + TTP
- 2bq1 - StRNR R1+ R2
- 5im3 - RNR + dATP – Pseudomonas aeruginosa

Class Ib RNR

- 6cgm - BaRNR subunit NrdE – Bacillus subtilis
- 6cgn, 6cgl - BaRNR subunit NrdE + AMP derivative
- 1pem - StRNR NrdE – Salmonella typhimurium
- 1peo, 1peq, 1peu - StRNR NrdE + nucleotide
- 2bq1 - StRNR NrdE + NrdF + Fe + GTP
- 4dr0 - BaRNR subunit NrdF + Mn
- 4bmq, 4bmr, 4bmt - BcRNR NrdF + Fe – Bacillus cereus
- 4bmu - BcRNR NrdF + Mn
- 4bmo, 4bmp - BcRNR NrdF + NrdI + Fe + FMN
- 4m1f - EcRNR NrdF
- 3n37 - EcRNR NrdF + Mn
- 3n38 - EcRNR NrdF + Fe
- 3n39, 3n3a - EcRNR NrdF + NrdI + Mn + FMN
- 3n3b - EcRNR NrdF + NrdI + Mn + FMN + Fe2O
- 4n82 – SsRNR + FMN – Streptococcus sanguinis
- 4n83 - SsRNR NrdF + Mn
- 1r2f - StRNR NrdF + Fe
- 2r2f - StRNR NrdF + Fe2O
- 3mjo - CcRNR NrdF + Mn - Corynebacterium ammoniagenes
- 1kgn, 1kgo, 1kgp, 1oqu, 3dhz - CcRNR NrdF + Fe
Class II ribonucleotide reductase
- 1xjf, 4col – TmRNR + DATP – Thermotoga maritima
- 4coi, 4com, 4con – TmRNR
- 1xjg, 1xjk, 1xje, 1xjn, 4coj - TmRNR + 2 nucleotides
- 1xjj - TmRNR + GTP
- 1xjm - TmRNR + TTP
- 3o0n - TmRNR + TTP + Co + Mg + deoxyadenosine + B12
- 3o0o - TmRNR + TTP + GDP + Mg + deoxyadenosine + B12
- 3o0q - TmRNR + TTP + GDP + Mg + adenosine
- 1l1l – RNR (mutant) – Lactobacillus leichmannii
Class III ribonucleotide reductase
- 1h78, 1h79, 1h7a, 1hk8 – T4RNR (mutant) + nucleotide triphosphate – bacteriophage T4
- 1h7b – T4RNR (mutant)
- 4u3e – TmRNR large subunit

ReferencesReferences

↑ Nordlund P, Reichard P. Ribonucleotide reductases. Annu Rev Biochem. 2006;75:681-706. PMID:16756507 doi:http://dx.doi.org/10.1146/annurev.biochem.75.103004.142443
↑ Cotruvo JA, Stubbe J. Class I ribonucleotide reductases: metallocofactor assembly and repair in vitro and in vivo. Annu Rev Biochem. 2011;80:733-67. doi: 10.1146/annurev-biochem-061408-095817. PMID:21456967 doi:http://dx.doi.org/10.1146/annurev-biochem-061408-095817
↑ Cotruvo JA, Stubbe J. Escherichia coli class Ib ribonucleotide reductase contains a dimanganese(III)-tyrosyl radical cofactor in vivo. Biochemistry. 2011 Mar 15;50(10):1672-81. doi: 10.1021/bi101881d. Epub 2011 Feb, 15. PMID:21250660 doi:http://dx.doi.org/10.1021/bi101881d
↑ Sintchak MD, Arjara G, Kellogg BA, Stubbe J, Drennan CL. The crystal structure of class II ribonucleotide reductase reveals how an allosterically regulated monomer mimics a dimer. Nat Struct Biol. 2002 Apr;9(4):293-300. PMID:11875520 doi:http://dx.doi.org/10.1038/nsb774
↑ Kirdis E, Jonsson IM, Kubica M, Potempa J, Josefsson E, Masalha M, Foster SJ, Tarkowski A. Ribonucleotide reductase class III, an essential enzyme for the anaerobic growth of Staphylococcus aureus, is a virulence determinant in septic arthritis. Microb Pathog. 2007 Nov-Dec;43(5-6):179-88. doi: 10.1016/j.micpath.2007.05.008., Epub 2007 May 25. PMID:17606358 doi:http://dx.doi.org/10.1016/j.micpath.2007.05.008
↑ Munro JB, Silva JC. Ribonucleotide reductase as a target to control apicomplexan diseases. Curr Issues Mol Biol. 2012;14(1):9-26. Epub 2011 Jul 26. PMID:21791713
↑ Larsson KM, Jordan A, Eliasson R, Reichard P, Logan DT, Nordlund P. Structural mechanism of allosteric substrate specificity regulation in a ribonucleotide reductase. Nat Struct Mol Biol. 2004 Nov;11(11):1142-9. Epub 2004 Oct 10. PMID:15475969 doi:http://dx.doi.org/10.1038/nsmb838

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Michal Harel, Jaime Prilusky, Alexander Berchansky, Joel L. Sussman

[1] Nordlund P, Reichard P. Ribonucleotide reductases. Annu Rev Biochem. 2006;75:681-706. PMID:16756507 doi:http://dx.doi.org/10.1146/annurev.biochem.75.103004.142443

[2] Cotruvo JA, Stubbe J. Class I ribonucleotide reductases: metallocofactor assembly and repair in vitro and in vivo. Annu Rev Biochem. 2011;80:733-67. doi: 10.1146/annurev-biochem-061408-095817. PMID:21456967 doi:http://dx.doi.org/10.1146/annurev-biochem-061408-095817

[3] Cotruvo JA, Stubbe J. Escherichia coli class Ib ribonucleotide reductase contains a dimanganese(III)-tyrosyl radical cofactor in vivo. Biochemistry. 2011 Mar 15;50(10):1672-81. doi: 10.1021/bi101881d. Epub 2011 Feb, 15. PMID:21250660 doi:http://dx.doi.org/10.1021/bi101881d

[4] Sintchak MD, Arjara G, Kellogg BA, Stubbe J, Drennan CL. The crystal structure of class II ribonucleotide reductase reveals how an allosterically regulated monomer mimics a dimer. Nat Struct Biol. 2002 Apr;9(4):293-300. PMID:11875520 doi:http://dx.doi.org/10.1038/nsb774

[5] Kirdis E, Jonsson IM, Kubica M, Potempa J, Josefsson E, Masalha M, Foster SJ, Tarkowski A. Ribonucleotide reductase class III, an essential enzyme for the anaerobic growth of Staphylococcus aureus, is a virulence determinant in septic arthritis. Microb Pathog. 2007 Nov-Dec;43(5-6):179-88. doi: 10.1016/j.micpath.2007.05.008., Epub 2007 May 25. PMID:17606358 doi:http://dx.doi.org/10.1016/j.micpath.2007.05.008

[6] Munro JB, Silva JC. Ribonucleotide reductase as a target to control apicomplexan diseases. Curr Issues Mol Biol. 2012;14(1):9-26. Epub 2011 Jul 26. PMID:21791713

[7] Larsson KM, Jordan A, Eliasson R, Reichard P, Logan DT, Nordlund P. Structural mechanism of allosteric substrate specificity regulation in a ribonucleotide reductase. Nat Struct Mol Biol. 2004 Nov;11(11):1142-9. Epub 2004 Oct 10. PMID:15475969 doi:http://dx.doi.org/10.1038/nsmb838

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