Skip to main content
SpringerLink
Log in

Ribozymes and the mechanisms that underlie RNA catalysis

  • Review Article
  • Published:
Frontiers of Chemical Science and Engineering Aims and scope Submit manuscript

Abstract

Ribozymes are widespread, and catalyze some extremely important reactions in the cell. Mechanistically most fall into one of two classes, using either metal ions or general acid-base catalysis. The nucleolytic ribozymes fall into the latter class, mostly using nucleobases. A sub-set of these use a combination of guanine base plus adenine acid to catalyze the cleavage reaction. New ribozymes are still being discovered at regular intervals and we can speculate on the potential existence of ribozymes that catalyze chemistry beyond phosphoryl transfer reactions, perhaps using small-molecule coenzymes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Noller H F, Hoffarth V, Zimniak L. Unusual resistance of peptidyl transferase to protein extraction procedures. Science, 1992, 256: 1416–1419

    Article  CAS  Google Scholar 

  2. Nissen P, Hansen J, Ba N, Moore P B, Steitz T A. The structural basis of ribosome activity in peptide bond synthesis. Science, 2000, 289: 920–930

    Article  CAS  Google Scholar 

  3. Weinger J S, Parnell K M, Dorner S, Green R, Strobel S A. Substrate-assisted catalysis of peptide bond formation by the ribosome. Nature Structural & Molecular Biology, 2004, 11: 1101–1106

    Article  CAS  Google Scholar 

  4. Kingery D A, Pfund E, Voorhees R M, Okuda K, Wohlgemuth I, Kitchen D E, RodninaMV, Strobel S A. An uncharged amine in the transition state of the ribosomal peptidyl transfer reaction. Chemistry & Biology, 2008, 15: 493–500

    Article  CAS  Google Scholar 

  5. Fica S M, Tuttle N, Novak T, Li N S, Lu J, Koodathingal P, Dai Q, Staley J P, Piccirilli J A. RNA catalyses nuclear pre-mRNA splicing. Nature, 2013, 503: 229–234

    CAS  Google Scholar 

  6. Keating K S, Toor N, Perlman P S, Pyle A M. A structural analysis of the group II intron active site and implications for the spliceosome. RNA (New York, N.Y.), 2010, 16: 1–9

    Article  Google Scholar 

  7. Guerrier-Takada C, Gardiner K, Marsh T, Pace N, Altman S. The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell, 1983, 35: 849–857

    Article  CAS  Google Scholar 

  8. Kikovska E, Svard S G, Kirsebom L A. Eukaryotic R Nase P RNA mediates cleavage in the absence of protein. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104: 2062–2067

    Article  CAS  Google Scholar 

  9. Przybilski R, Graf S, Lescoute A, Nellen W, Westhof E, Steger G, Hammann C. Functional hammerhead ribozymes naturally encoded in the genome of Arabidopsis thaliana. Plant Cell, 2005, 17: 1877–1885

    Article  CAS  Google Scholar 

  10. Seehafer C, Kalweit A, Steger G, Graf S, Hammann C. From alpaca to zebrafish: Hammerhead ribozymes wherever you look. RNA (New York, N.Y.), 2011, 17: 21–26

    Article  CAS  Google Scholar 

  11. Salehi-Ashtiani K, Luptak A, Litovchick A, Szostak J W. A genomewide search for ribozymes reveals an HDV-like sequence in the human CPEB3 gene. Science, 2006, 313: 1788–1792

    Article  CAS  Google Scholar 

  12. Webb C H, Riccitelli N J, Ruminski D J, Luptak A. Widespread occurrence of self-cleaving ribozymes. Science, 2009, 326: 953

    Article  CAS  Google Scholar 

  13. Roth A, Weinberg Z, Chen A G, Kim P B, Ames T D, Breaker R R. A widespread self-cleaving ribozyme class is revealed by bioinformatics. Nature Chemical Biology, 2014, 10: 56–60

    Article  CAS  Google Scholar 

  14. Weinberg Z, Kim P B, Chen T H, Li S, Harris K A, Lunse C E, Breaker R R. New classes of self-cleaving ribozymes revealed by comparative genomics analysis. Nature Chemical Biology, 2015, 11: 606–610

    Article  CAS  Google Scholar 

  15. Lilley D M, Sutherland J. The chemical origins of life and its early evolution: An introduction. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 2011, 366: 2853–2856

    Article  CAS  Google Scholar 

  16. Crick F H C. The origin of the genetic code. Journal of Molecular Biology, 1968, 38: 367–379

    Article  CAS  Google Scholar 

  17. Orgel L E. RNA catalysis and the origin of life. Journal of Theoretical Biology, 1986, 123: 127–149

    Article  CAS  Google Scholar 

  18. Wilson T J, Lilley D M J. The evolution of ribozyme chemistry. Science, 2009, 323: 1436–1438

    Article  CAS  Google Scholar 

  19. Adams P L, StahleyMR, Wang J, Strobel S A. Crystal structure of a self-splicing group I intron with both exons. Nature, 2004, 430: 45–50

    Article  CAS  Google Scholar 

  20. Marcia M, Pyle A M. Visualizing group II intron catalysis through the stages of splicing. Cell, 2012, 151: 497–507

    Article  CAS  Google Scholar 

  21. Steitz T A, Steitz J A. A general 2-metal-ion mechanism for catalytic RNA. Proceedings of the National Academy of Sciences of the United States of America, 1993, 90: 6498–6502

    Article  CAS  Google Scholar 

  22. Shan S, Kravchuk A V, Piccirilli J A, Herschlag D. Defining the catalytic metal ion interactions in the Tetrahymena ribozyme reaction. Biochemistry, 2001, 40: 5161–5171

    Article  CAS  Google Scholar 

  23. Hougland J L, Kravchuk A V, Herschlag D, Piccirilli J A. Functional identification of catalytic metal ion binding sites within RNA. PLoS Biology, 2005, 3: e277

    Article  Google Scholar 

  24. Frederiksen J K, Li N S, Das R, Herschlag D, Piccirilli J A. Metalion rescue revisited: Biochemical detection of site-bound metal ions important for RNA folding. RNA (New York, N.Y.), 2012, 18: 1123–1141

    Article  CAS  Google Scholar 

  25. Golden B L, Gooding A R, Podell E, Cech T R. A preorganised active site in the crystal structure of the Tetrahymena ribozyme. Science, 1998, 282: 259–264

    Article  CAS  Google Scholar 

  26. Stahley M R, Strobel S A. Structural evidence for a two-metal-ion mechanism of group I intron splicing. Science, 2005, 309: 1587–1590

    Article  CAS  Google Scholar 

  27. Golden B L, Kim H D, Chase E. Crystal structure of a phage Twort group I ribozyme-product complex. Nature Structural & Molecular Biology, 2005, 12: 82–89

    Article  CAS  Google Scholar 

  28. Toor N, Keating K S, Taylor S D, Pyle A M. Crystal structure of a self-spliced group II intron. Science, 2008, 320: 77–82

    Article  CAS  Google Scholar 

  29. Gordon P M, Sontheimer E J, Piccirilli J A. Metal ion catalysis during the exon-ligation step of nuclear pre-mRNA splicing: Extending the parallels between the spliceosome and group II introns. RNA (New York, N.Y.), 2000, 6: 199–205

    Article  CAS  Google Scholar 

  30. Huppler A, Nikstad L J, Allmann A M, Brow D A, Butcher S E. Metal binding and base ionization in the U6 RNA intramolecular stem-loop structure. Nature Structural Biology, 2002, 9: 431–435

    Article  CAS  Google Scholar 

  31. Kazantsev A V, Krivenko A A, Pace N R. Mapping metal-binding sites in the catalytic domain of bacterial R Nase P RNA. RNA (New York, N.Y.), 2009, 15: 266–276

    Article  CAS  Google Scholar 

  32. Thompson J E, Raines R T. Value of general acid-base catalysis to Ribonuclease A. Journal of the American Chemical Society, 1994, 116: 5467–5468

    Article  CAS  Google Scholar 

  33. Raines R T, Ribonuclease A. Chemical Reviews, 1998, 98: 1045–1066

    Article  CAS  Google Scholar 

  34. Rupert P B, Ferré-D’Amaré A R. Crystal structure of a hairpin ribozyme-inhibitor complex with implications for catalysis. Nature, 2001, 410: 780–786

    Article  CAS  Google Scholar 

  35. Ke A, Zhou K, Ding F, Cate J H, Doudna J A. A conformational switch controls hepatitis delta virus ribozyme catalysis. Nature, 2004, 429: 201–205

    Article  CAS  Google Scholar 

  36. Martick M, Scott W G. Tertiary contacts distant from the active site prime a ribozyme for catalysis. Cell, 2006, 126: 309–320

    Article  CAS  Google Scholar 

  37. Klein D J, Ferré-D’Amaré A R. Structural basis of glmS ribozyme activation by glucosamine-6-phosphate. Science, 2006, 313: 1752–1756

    Article  CAS  Google Scholar 

  38. Cochrane J C, Lipchock S V, Strobel S A. Structural investigation of the GlmS ribozyme bound to its catalytic cofactor. Chemistry & Biology, 2007, 14: 97–105

    Article  CAS  Google Scholar 

  39. Liu Y, Wilson T J, McPhee S A, Lilley D M. Crystal structure and mechanistic investigation of the twister ribozyme. Nature Chemical Biology, 2014, 10: 739–744

    Article  CAS  Google Scholar 

  40. Eiler D, Wang J, Steitz T A. Structural basis for the fast self-cleavage reaction catalyzed by the twister ribozyme. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111: 13028–13033

    Article  CAS  Google Scholar 

  41. Ren A, Kosutic M, Rajashankar K R, Frener M, Santner T, Westhof E, Micura R, Patel D J. In-line alignment and Mg2+ coordination at the cleavage site of the env22 twister ribozyme. Nature Communications, 2014, 5: 5534

    Article  CAS  Google Scholar 

  42. Suslov N B, Das Gupta S, Huang H, Fuller J R, Lilley D M, Rice P A, Piccirilli J A. Crystal structure of the Varkud satellite ribozyme. Nature Chemical Biology, 2015, 11: 840–846

    Article  CAS  Google Scholar 

  43. Han J, Burke J M. Model for general acid-base catalysis by the hammerhead ribozyme: pH-activity relationships of G8 and G12 variants at the putative active site. Biochemistry, 2005, 44: 7864–7870

    Article  CAS  Google Scholar 

  44. Klein D J, Been M D, Ferré-D’Amaré A R. Essential role of an active-site guanine in glmS ribozyme catalysis. Journal of the American Chemical Society, 2007, 129: 14858–14859

    Article  CAS  Google Scholar 

  45. Wilson T J, Mc Leod A C, Lilley D M J. A guanine nucleobase important for catalysis by the VS ribozyme. EMBO Journal, 2007, 26: 2489–2500

    Article  CAS  Google Scholar 

  46. Cochrane J C, Lipchock S V, Smith K D, Strobel S A. Structural and chemical basis for glucosamine 6-phosphate binding and activation of the glmS ribozyme. Biochemistry, 2009, 48: 3239–3246

    Article  CAS  Google Scholar 

  47. Kath-Schorr S, Wilson T J, Li N S, Lu J, Piccirilli J A, Lilley D M. General acid-base catalysis mediated by nucleobases in the hairpin ribozyme. Journal of the American Chemical Society, 2012, 134: 16717–16724

    Article  CAS  Google Scholar 

  48. Lafontaine D A, Wilson T J, Norman D G, Lilley D M J. The A730 loop is an important component of the active site of the VS ribozyme. Journal of Molecular Biology, 2001, 312: 663–674

    Article  CAS  Google Scholar 

  49. Rupert P B, Massey A P, Sigurdsson S T, Ferré-D’Amaré A R. Transition state stabilization by a catalytic RNA. Science, 2002, 298: 1421–1424

    Article  CAS  Google Scholar 

  50. Wilson T J, Li N S, Lu J, Frederiksen J K, Piccirilli J A, Lilley D M J. Nucleobase-mediated general acid-base catalysis in the Varkud satellite ribozyme. Proceedings of the National Academy of Sciences of the United States of America, 2010, 107: 11751–11756

    Article  CAS  Google Scholar 

  51. Wilson T J, Lilley D M J. Do the hairpin and VS ribozymes share a common catalytic mechanism based on general acid-base catalysis? A critical assessment of available experimental data. RNA (New York, N.Y.), 2011, 17: 213–221

    Article  CAS  Google Scholar 

  52. Nakano S, Chadalavada D M, Bevilacqua P C. General acid-base catalysis in the mechanism of a hepatitis delta virus ribozyme. Science, 2000, 287: 1493–1497

    Article  CAS  Google Scholar 

  53. Das S R, Piccirilli J A. General acid catalysis by the hepatitis delta virus ribozyme. Nature Chemical Biology, 2005, 1: 45–52

    Article  CAS  Google Scholar 

  54. Chen J H, Yajima R, Chadalavada D M, Chase E, Bevilacqua P C, Golden B L A. 1.9 A crystal structure of the HDV ribozyme precleavage suggests both Lewis acid and general acid mechanisms contribute to phosphodiester cleavage. Biochemistry, 2010, 49: 6508–6518

    Article  CAS  Google Scholar 

  55. McCarthy T J, Plog MA, Floy S A, Jansen J A, Soukup J K, Soukup G A. Ligand requirements for glmS ribozyme self-cleavage. Chemistry & Biology, 2005, 12: 1221–1226

    Article  CAS  Google Scholar 

  56. Winkler W C, Nahvi A, Roth A, Collins J A, Breaker R R. Control of gene expression by a natural metabolite-responsive ribozyme. Nature, 2004, 428: 281–286

    Article  CAS  Google Scholar 

  57. Prody G A, Bakos J T, Buzayan J M, Schneider I R, Bruening G. Autolytic processing of dimeric plant virus satellite RNA. Science, 1986, 231: 1577–1580

    Article  CAS  Google Scholar 

  58. Forster A C, Symons R H. Self-cleavage of plus and minus RNAs of a virusoid and a structural model for the active sites. Cell, 1987, 49: 211–220

    Article  CAS  Google Scholar 

  59. Lee T S, Silva L C, Giambasu G M, Martick M, Scott W G, York D M. Role of Mg2+ in hammerhead ribozyme catalysis from molecular simulation. Journal of the American Chemical Society, 2008, 130: 3053–3064

    Article  CAS  Google Scholar 

  60. Thomas J M, Perrin D M. Probing general acid catalysis in the hammerhead ribozyme. Journal of the American Chemical Society, 2009, 131: 1135–1143

    Article  CAS  Google Scholar 

  61. Johnston W K, Unrau P J, Lawrence M S, Glasner M E, Bartel D P. RNA-catalyzed RNA polymerization: Accurate and general RNAtemplated primer extension. Science, 2001, 292: 1319–1325

    Article  CAS  Google Scholar 

  62. Robertson M P, Joyce G F. Highly efficient self-replicating RNA enzymes. Chemistry & Biology, 2014, 21: 238–245

    Article  CAS  Google Scholar 

  63. Attwater J, Wochner A, Holliger P. In-ice evolution of RNA polymerase ribozyme activity. Nature Chemistry, 2013, 5: 1011–1018

    Article  CAS  Google Scholar 

  64. Ekland E H, Szostak J W, Bartel D P. Structurally complex and highly active RNA ligases derived from random RNA sequences. Science, 1995, 269: 364–370

    Article  CAS  Google Scholar 

  65. Shechner D M, Grant R A, Bagby S C, Koldobskaya Y, Piccirilli J A, Bartel D P. Crystal structure of the catalytic core of an RNApolymerase ribozyme. Science, 2009, 326: 1271–1275

    Article  CAS  Google Scholar 

  66. Sengle G, Eisenfuhr A, Arora P S, Nowick J S, Famulok M. Novel RNA catalysts for the Michael reaction. Chemistry & Biology, 2001, 8: 459–473

    Article  CAS  Google Scholar 

  67. Fusz S, Eisenfuhr A, Srivatsan S G, Heckel A, Famulok M. A ribozyme for the aldol reaction. Chemistry & Biology, 2005, 12: 941–950

    Article  CAS  Google Scholar 

  68. Oberhuber M, Joyce G F. A DNA-templated aldol reaction as a model for the formation of pentose sugars in the RNA world. Angewandte Chemie, 2005, 44: 7580–7583

    Article  CAS  Google Scholar 

  69. Seelig B, Jäschke A. A small catalytic RNA motif with Diels- Alderase activity. Chemistry & Biology, 1999, 6: 167–176

    Article  CAS  Google Scholar 

  70. Benner S A, Ellington A D, Tauer A. Modern metabolism as a palimpsest of the RNA world. Proceedings of the National Academy of Sciences of the United States of America, 1989, 86: 7054–7058

    Article  CAS  Google Scholar 

  71. Jadhav V R, Yarus M. Coenzymes as coribozymes. Biochimie, 2002, 84: 877–888

    Article  CAS  Google Scholar 

  72. Breaker R R. Prospects for riboswitch discovery and analysis. Molecular Cell, 2011, 43: 867–879

    Article  CAS  Google Scholar 

  73. Winkler W C, Breaker R R. Genetic control by metabolite-binding riboswitches. ChemBioChem, 2003, 4: 1024–1032

    Article  CAS  Google Scholar 

  74. Winkler W, Nahvi A, Breaker R R. Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression. Nature, 2002, 419: 952–956

    Article  CAS  Google Scholar 

  75. Wang J, Daldrop P, Huang L, Lilley D M. The k-junction motif in RNA structure. Nucleic Acids Research, 2014, 42: 5322–5331

    Article  CAS  Google Scholar 

  76. Thore S, Leibundgut M, Ban N. Structure of the eukaryotic thiamine pyrophosphate riboswitch with its regulatory ligand. Science, 2006, 312: 1208–1211

    Article  CAS  Google Scholar 

  77. Serganov A, Polonskaia A, Phan A T, Breaker R R, Patel D J. Structural basis for gene regulation by a thiamine pyrophosphatesensing riboswitch. Nature, 2006, 441: 1167–1171

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Research UK Nucleic Acid Structure Research Group, MSI/WTB Complex, The University of Dundee, Dundee, DD1 5EH, UK

    Timothy J. Wilson, Yijin Liu & David M. J. Lilley

Authors
  1. Timothy J. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yijin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David M. J. Lilley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David M. J. Lilley.

Additional information

David Lilley FRS is Professor and Director of the CRUK Nucleic Acids Research Group at the University of Dundee, UK. He combines structural, biophysical and mechanistic studies to explore the origins of chemical catalysis in the ribozymes. His laboratory has made significant contributions to the structure and catalytic mechanisms of the VS, hairpin, hammerhead and most recently the twister ribozymes. More widely, his laboratory also studies nucleic acid structure and folding. This includes the widespread kink-turn motif in RNA and the Holliday four-way junction in DNA. His laboratory has recently presented the crystal structure of the eukaryotic junction-resolving enzyme GEN1 bound to the product of junction resolution. In addition to structural studies, the Lilley laboratory uses single-molecule analysis of nucleic acid dynamics, and has analyzed the photophysics of cyanine fluorophores to yield orientational information from fluorescence resonance energy transfer in single molecules. Professor Lilley has extensive links with Chinese institutions, including an appointment as a visiting professor at Xiamen University in Fujian Province.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wilson, T.J., Liu, Y. & Lilley, D.M.J. Ribozymes and the mechanisms that underlie RNA catalysis. Front. Chem. Sci. Eng. 10, 178–185 (2016). https://doi.org/10.1007/s11705-016-1558-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11705-016-1558-2

Keywords

Search

Navigation