Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

RNA with iron(II) as a cofactor catalyses electron transfer

Abstract

Mg2+ is essential for RNA folding and catalysis. However, for the first 1.5 billion years of life on Earth RNA inhabited an anoxic Earth with abundant and benign Fe2+. We hypothesize that Fe2+ was an RNA cofactor when iron was abundant, and was substantially replaced by Mg2+ during a period known as the ‘great oxidation’, brought on by photosynthesis. Here, we demonstrate that reversing this putative metal substitution in an anoxic environment, by removing Mg2+ and replacing it with Fe2+, expands the catalytic repertoire of RNA. Fe2+ can confer on some RNAs a previously uncharacterized ability to catalyse single-electron transfer. We propose that RNA function, in analogy with protein function, can be understood fully only in the context of association with a range of possible metals. The catalysis of electron transfer, requisite for metabolic activity, may have been attenuated in RNA by photosynthesis and the rise of O2.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Some RNAs in combination with Fe2+ catalyse single-electron transfer.
Figure 2: Fe2+–RNA catalysed single-electron transfer reactions follow enzyme kinetics.

References

  1. 1

    Anbar, A. D. Oceans. Elements and evolution. Science 322, 1481–1483 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Hazen, R. M. & Ferry, J. M. Mineral evolution: mineralogy in the fourth dimension. Elements 6, 9–12 (2010).

    CAS  Article  Google Scholar 

  3. 3

    Prousek, J. Fenton chemistry in biology and medicine. Pure Appl. Chem. 79, 2325–2338 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Klein, C. Some Precambrian banded iron-formations (BIFs) from around the world: their age, geologic setting, mineralogy, metamorphism, geochemistry, and origin. Am. Mineral. 90, 1473–1499 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Aguirre, J. D. & Culotta, V. C. Battles with iron: manganese in oxidative stress protection. J. Biol. Chem. 287, 13541–13548 (2012).

    CAS  Article  Google Scholar 

  6. 6

    Ushizaka, S., Kuma, K. & Suzuki, K. Effects of Mn and Fe on growth of a coastal marine diatom Thalassiosira weissflogii in the presence of precipitated Fe(III) hydroxide and EDTA–Fe(III) complex. Fish. Sci. 77, 411–424 (2011).

    CAS  Article  Google Scholar 

  7. 7

    Martin, J. E. & Imlay, J. A. The alternative aerobic ribonucleotide reductase of Escherichia coli, NrdEF, is a manganese-dependent enzyme that enables cell replication during periods of iron starvation. Mol. Microbiol. 80, 319–334 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Cotruvo, J. A. & Stubbe, J. Class I ribonucleotide reductases: metallocofactor assembly and repair in vitro and in vivo. Annu. Rev. Biochem. 80, 733–767 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Anjem, A., Varghese, S. & Imlay, J. A. Manganese import is a key element of the OxyR response to hydrogen peroxide in Escherichia coli. Mol. Microbiol. 72, 844–858 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Wolfe-Simon, F., Starovoytov, V., Reinfelder, J. R., Schofield, O. & Falkowski, P. G. Localization and role of manganese superoxide dismutase in a marine diatom. Plant Physiol. 142, 1701–1709 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Jordan, A. & Reichard, P. Ribonucleotide reductases. Annu. Rev. Biochem. 67, 71–98 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Athavale, S. S. et al. RNA folding and catalysis mediated by iron(II). PLoS ONE 7, e38024 (2012).

    CAS  Article  Google Scholar 

  13. 13

    Fox, G. E. Origin and evolution of the ribosome. Cold Spring Harb. Perspect. Biol. 2, a003483 (2010).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Bowman, J. C., Lenz, T. K., Hud, N. V. & Williams, L. D. Cations in charge: magnesium ions in RNA folding and catalysis. Curr. Opin. Struct. Biol. 22, 262–272 (2012).

    CAS  Article  Google Scholar 

  15. 15

    Auffinger, P., Grover, N. & Westhof, E. Metal ion binding to RNA. Met. Ions Life Sci. 9, 1–35 (2011).

    CAS  PubMed  Google Scholar 

  16. 16

    Brion, P. & Westhof, E. Hierarchy and dynamics of RNA folding. Annu. Rev. Biophys. Biomol. Struct. 26, 113–137 (1997).

    CAS  Article  Google Scholar 

  17. 17

    Stein, A. & Crothers, D. M. Conformational changes of transfer RNA. The role of magnesium(II). Biochemistry 15, 160–168 (1976).

    CAS  Article  Google Scholar 

  18. 18

    Lynch, D. C. & Schimmel, P. R. Cooperative binding of magnesium to transfer ribonucleic acid studied by a fluorescent probe. Biochemistry 13, 1841–1852 (1974).

    CAS  Article  Google Scholar 

  19. 19

    Lindahl, T., Adams, A. & Fresco, J. R. Renaturation of transfer ribonucleic acids through site binding of magnesium. Proc. Natl Acad. Sci. USA 55, 941–948 (1966).

    CAS  Article  Google Scholar 

  20. 20

    Petrov, A. et al. RNA–magnesium–protein interactions in large ribosomal subunit. J. Phys. Chem. B 116, 8113–8120 (2012).

    CAS  Article  Google Scholar 

  21. 21

    Butcher, S. E. The spliceosome and its metal ions. Met. Ions Life Sci. 9, 235–251 (2011).

    CAS  Article  Google Scholar 

  22. 22

    Johnson-Buck, A. E., McDowell, S. E. & Walter, N. G. Metal ions: supporting actors in the playbook of small ribozymes. Met. Ions Life Sci. 9, 175–196 (2011).

    CAS  Article  Google Scholar 

  23. 23

    Josephy, P. D., Eling, T. & Mason, R. P. The horseradish peroxidase-catalyzed oxidation of 3,5,3′,5′-tetramethylbenzidine. Free radical and charge–transfer complex intermediates. J. Biol. Chem. 257, 3669–3675 (1982).

    CAS  PubMed  Google Scholar 

  24. 24

    Larson, S. B., Day, J., Greenwood, A. & McPherson, A. Refined structure of satellite tobacco mosaic virus at 1.8 Å resolution. J. Mol. Biol. 277, 37–59 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Hsiao, C. & Williams, L. D. A recurrent magnesium-binding motif provides a framework for the ribosomal peptidyl transferase center. Nucleic Acids Res. 37, 3134–3142 (2009).

    CAS  Article  Google Scholar 

  26. 26

    Klein, D. J., Moore, P. B. & Steitz, T. A. The contribution of metal ions to the structural stability of the large ribosomal subunit. RNA 10, 1366–1379 (2004).

    CAS  Article  Google Scholar 

  27. 27

    Cate, J. H., Hanna, R. L. & Doudna, J. A. A magnesium ion core at the heart of a ribozyme domain. Nature Struct. Biol. 4, 553–558 (1997).

    CAS  Article  Google Scholar 

  28. 28

    Berens, C., Streicher, B., Schroeder, R. & Hillen, W. Visualizing metal–ion-binding sites in group I introns by iron(II)-mediated Fenton reactions. Chem. Biol. 5, 163–175 (1998).

    CAS  Article  Google Scholar 

  29. 29

    Zivarts, M., Liu, Y. & Breaker, R. R. Engineered allosteric ribozymes that respond to specific divalent metal ions. Nucleic Acids Res. 33, 622–631 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Ma, J. et al. Fe2+ binds iron responsive element-RNA, selectively changing protein-binding affinities and regulating mRNA repression and activation. Proc. Natl Acad. Sci. USA 109, 8417–8422 (2012).

    CAS  Article  Google Scholar 

  31. 31

    Honda, K. et al. Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J. Biol. Chem. 280, 20978–20986 (2005).

    CAS  Article  Google Scholar 

  32. 32

    Tsukiji, S., Pattnaik, S. B. & Suga, H. Reduction of an aldehyde by a NADH/Zn2+-dependent redox active ribozyme. J. Am. Chem. Soc. 126, 5044–5045 (2004).

    CAS  Article  Google Scholar 

  33. 33

    Sen, D. & Poon, L. C. RNA and DNA complexes with hemin [Fe(III) heme] are efficient peroxidases and peroxygenases: how do they do it and what does it mean? Crit. Rev. Biochem. Mol. Biol. 46, 478–492 (2011).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors thank J. Bada, R. Hazen, K. Barefield, J. Sadighi and D. Jenson for helpful discussions. This work was supported by the National Aeronautics and Space Administration Astrobiology Institute (NNA09DA78A).

Author information

Affiliations

Authors

Contributions

C.H., N.V.H, R.M.W., S.C.H. and L.D.W. conceived and designed the experiments and co-wrote the manuscript. C.H., C.D.O. and I-C.C. performed the experiments and analysed the data. J.C.B., E.B.O'N, S.S.A. and A.P. contributed materials and analysis tools. All the authors discussed the results and contributed to writing and editing the manuscript.

Corresponding author

Correspondence to Loren Dean Williams.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 588 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hsiao, C., Chou, IC., Okafor, C. et al. RNA with iron(II) as a cofactor catalyses electron transfer. Nature Chem 5, 525–528 (2013). https://doi.org/10.1038/nchem.1649

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing