Britt-Marie SjöbergProfessor

The ribonucleotide reductase enzyme family

Organisms store their genetic information in DNA, and the enzyme ribonucleotide reductase (RNR) catalyses the reaction that provides new DNA building blocks. RNR is therefore a prerequisite in all living cells, and also regulates cellular replication and proliferation. Some antiproliferative drugs (e.g. hydroxyurea and gemcitabine) that are used clinically today are specific inhibitors of RNR.

There are currently three different classes of RNRs (I, II, and III) that differ in reactivity towards oxygen, cofactor requirement, and quaternary structure. Our database RNRdb also distinguishes several RNR subclasses. Despite the striking differences all RNRs appear to have a common evolutionary origin.

Current projects are:

• understanding the evolution of extant RNRs
• understanding the structure and function of the RNR-specific transcriptional repressor NrdR
• developing novel antibiotics towards NrdR and RNRs in pathogenic microorganisms
• understanding the emergence of ribonucleotide reduction in the RNP (RNA+protein) world

Group members

Inna Rozman Grinberg, Researcher

Selected Publications

• Bimaï O, Banerjee I, Rozman Grinberg I, Huang P, Hultgren L, Ekström S, Lundin D, Sjöberg BM & Logan DT. Nucleotide binding to the ATP-cone in anaerobic ribonucleotide reductase allosterically regulates activity by modulating substrate binding. (2024) eLife 12:RP89292 https://doi.org/10.7554/eLife.89292.
• Lebrette H, Srinivas V, John J, Aurelius O, Kumar R, Lundin D, Brewster AS, Bhowmick A, Sirohiwal A, Kim IS, Gul S, Pham C, Sutherlin KD, Simon P, Butryn A, Aller P, Orville AM, Fuller FD, Alonso-Mori R, Batyuk A, Sauter NK, Yachandra VK, Yano J, Kaila VRI, Sjöberg BM, Kern J, Roos K, Högbom M. Structure of a ribonucleotide reductase R2 protein radical. (2023) Science 382:109-113. https://doi.org/10.1126/science.adh8160
• Rozman Grinberg I, Martínez-Carranza M, Bimai O, Nouaïria G, Shahid S, Lundin D, Logan DT, Sjöberg BM, Stenmark P. A nucleotide-sensing oligomerization mechanism that controls NrdR-dependent transcription of ribonucleotide rerductases. (2022) Nat Commun, May 16; 13(1):2700. https://doi.org/10.1038/s41467-022-30328-1.
• Rehling D, Rose Scaletti E, Rozman Grinberg I, Lundin D, Sahlin M, Hofer A, Sjöberg B-M and Stenmark P. Structural and biochemical investigation of class I ribonucleotide reductase from the hyperthermophile Aquifex aeolicus. (2022) Biochemistry 61(2): 92–106. Epub: December 23, 2021 https://doi.org/10.1021/acs.biochem.1c00503
• Hasan M, Banerjee I, Rozman Grinberg I, Sjöberg BM & Logan DT. Solution structure of the dATP-inactivated classI ribonucleotide reductase from Leeuwenhoekiella blandensis by SAXS and cryo- electron microscopy (2021) Front Mol Biosci, 8:713608. https://doi.org/10.3389/fmolb.2021.713608
• Högbom M, Sjöberg BM & Berggren G. Radical enzymes (2020) eLS, 1: 375–393. Online Sept 30. https://doi.org/10.100279780470015902.a00292025
• Martínez-Carranza M, Jonna VR, Lundin D, Sahlin M, Carlson LA, Jemal N, Högbom M, Sjöberg BM, Stenmark P & Hofer A. A ribonucleotide reductase from Clostridium botulinum reveals distinct evolutionary pathways to regulation via the overall activity site. J Biol Chem (2020) 295: 15576-15587. https://www.jbc.org/content/295/46/15576
• Rozman Grinberg I, Berglund S, Hasan M, Lundin D, Ho FM, Magnuson A, Logan DT, Sjöberg BM & Berggren G. Class Id ribonucleotide reductase utilizes a Mn2(IV,III) cofactor and undergoes large conformational changes on metal loading. J Biol Inorg Chem (2019) https://doi.org/10.1007/s00775-019-01697-8 (Part of the following topical collections: Joan Broderick: Papers in Celebration of Her 2019 ACS Alfred Bader Award in Bioinorganic or Bioorganic Chemistry)
• Berggren G, Sahlin M, Crona M, Tholander F & Sjöberg, BM. Compounds with capacity to quench the tyrosyl radical in Pseudomonas aeruginosa ribonucleotide reductase. J Biol Inorg Chem (2019) https://doi.org/10.1007/s00775-019-01679-w (Part of the following topical collections: Joan Broderick: Papers in Celebration of Her 2019 ACS Alfred Bader Award in Bioinorganic or Bioorganic Chemistry)
• Srinivas V, Lebrette H, Lundin L, Kutin Y, Sahlin M, Lerche M, Eirich J, Branca RMM, Cox N, Sjöberg BM & Högbom M. Metal-free ribonucleotide reduction powered by a DOPA radical in Mycoplasma  pathogens. Nature (2018) 563: 416-420. Additional information at SU news.
• Rozman Grinberg I, Lundin D, Sahlin M, Crona M, Berggren G, Hofer A & Sjöberg BM. A glutaredoxin domain fused to the radical-generating subunit of ribonucleotide reductase (RNR) functions as an efficient RNR reductant. J Biol Chem (2018) 293: 15889-15900.
• Rozman Grinberg I, Lundin D. Hasan M, Crona M, Jonna VR, Loderer C, Sahlin M, Markova 
N, Borovok I, Berggren G, Hofer A, Logan DT & 
Sjöberg, BM. Novel ATP-cone-driven allosteric regulation of ribonucleotide 
reductase via the radical-generating subunit. eLife (2018) 7: e31529. Additional information at SU news.
• Loderer C, Jonna VR, Crona M, Rozman Grinberg I, Sahlin M, Hofer A, Lundin D, Sjöberg BM. A unique cysteine-rich Zn-finger domain present in a majority of class II ribonucleotide reductases mediates catalytic turnover. J Biol Chem. (2017) 292: 19044-19054 (selected as Recommended Reads by the Editors).
• Berggren G, Lundin D, Sjöberg BM. Homo- and heterometallic dinuclear manganese proteins: active site assembly. In: Encyclopedia of Inorganic and Bioinorganic Chemistry, edited by Robert A. Scott. John Wiley & Sons, Ltd: Chichester, UK (2017). doi: 10.1002/9781119951438.eibc2480.
• Johansson, R., Rao Jonna, V., Kumar, R., Nayeri, N., Lundin, D., Sjöberg, BM., Hofer, A. & Logan, D.T. Structural mechanism of allosteric activity regulation in a ribonucleotide reductase with double ATP cones, Structure (2016) 24: 906-917.
• Crona, M., Hofer, A., Astorga-Wells, J., Sjöberg, BM. & Tholander, F. Biochemical characterization of the split class II ribonucleotide reductase from Pseudomonas aeruginosa. PLoS One (2015) 10: e0134293
• Rao Jonna, V., Crona, M., Rofougaran, R., Lundin, D., Johansson, S., Brännström, K., Sjöberg, B.-M. & Hofer, A. Diversity in overall activity regulation of ribonucleotide reductase. J Biol Chem (2015) 290: 17339-17348.
• Aurelius, O., Johansson, R., Bågenholm, V., Lundin, D., Tholander, F., Balhuizen, A., Beck, T., Sahlin, M., Sjöberg, B.-M., Mulliez, E. & Logan D.T. The crystal structure of Thermotoga maritima class III ribonucleotide reductase lacks a radical cysteine pre-positioned in the active site. PLoS One (2015) 10: e0128199.
• Lundin, D., Berggren, G., Logan, D.T. & Sjöberg, B.-M. The origin and evolution of ribonucleotide reduction. Life (Basel) (2015) 5, 604-36.
• Berggren, G., Duraffourg, N., Sahlin, M. & Sjöberg, B.-M. Semiquinone-induced maturation of Bacillus anthracis ribonucleotide reductase by a superoxide intermediate. J Biol Chem (2014) 289: 31940-9.
• Crona, M., Avesson, L., Sahlin, M., Lundin, D., Hinas, A., Klose, R., Söderbom, F & Sjöberg, B.-M. A rare combination of ribonucleotide reductases in the social amoeba Dictyostelium discoideum. J Biol Chem (2013) 288:8198-208.
• Tholander, F. & Sjöberg, B.-M. Discovery of antimicrobial ribonucleotide reductase inhibitors by screening in microwell format. Proc Natl Acad Sci USA (2012) 109: 9798-803.
• Lundin, D., Poole, A.M., Sjöberg, B.-M. & Högbom, M. Use of structural phylogenetic networks for classification of the ferritin-like superfamily. J Biol Chem (2012) 287: 20565-75.
• Hofer, A., Crona, M., Logan, D.T. & Sjöberg, B.-M. DNA building blocks: keeping control of manufacture. Critical Rev Biochem Mol Biol (2012) 47: 50-63.
• Lundin D, Gribaldo S, Torrents E, Sjöberg B-M & Poole AM. Ribonucleotide reduction - horizontal transfer of a required function spans all three domains. BMC Evolutionary Biology (2010) 10:383 (selected “highly accessed” by the editors of BMC Evol Biol)
• Sjöberg B-M. A never-ending story. Science (2010) 329: 1475-1476.

Funding Sources

The Swedish Research Council, The Swedish Cancer Foundation, The Wenner-Gren Foundations