Abstract
RNA molecules are thought to have been prominent in the early history of life on Earth because of their ability both to encode genetic information and to exhibit catalytic function1. The modern genetic alphabet relies on two sets of complementary base pairs to store genetic information. However, owing to the chemical instability of cytosine, which readily deaminates to uracil2, a primitive genetic system composed of the bases A, U, G and C may have been difficult to establish. It has been suggested that the first genetic material instead contained only a single base-pairing unit3,4,5,6,7. Here we show that binary informational macromolecules, containing only two different nucleotide subunits, can act as catalysts. In vitro evolution was used to obtain ligase ribozymes composed of only 2,6-diaminopurine and uracil nucleotides, which catalyse the template-directed joining of two RNA molecules, one bearing a 5′-triphosphate and the other a 3′-hydroxyl. The active conformation of the fastest isolated ribozyme had a catalytic rate that was about 36,000-fold faster than the uncatalysed rate of reaction. This ribozyme is specific for the formation of biologically relevant 3′,5′-phosphodiester linkages.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Gesteland, R. F., Cech, T. R. & Atkins, J. F. (eds) The RNA World 2nd edn (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1999)
Levy, M. & Miller, S. L. The stability of the RNA bases: implications for the origin of life. Proc. Natl Acad. Sci. USA 95, 7933–7938 (1998)
Rich, A. Horizons in Biochemistry (eds Kasha, M. & Pullman, B.) 103–126 (Academic, New York, 1962)
Crick, F. H. C. The origin of the genetic code. J. Mol. Biol. 38, 367–379 (1968)
Orgel, L. E. Evolution of the genetic apparatus. J. Mol. Biol. 38, 381–393 (1968)
Wächtershäuser, G. An all-purine precursor of nucleic acids. Proc. Natl Acad. Sci. USA 85, 1134–1135 (1988)
Zubay, G. An all-purine precursor of nucleic acids. Chemtracts, 2, 439–442 (1991)
Rogers, J. & Joyce, G. F. A ribozyme that lacks cytidine. Nature 402, 323–325 (1999)
Rogers, J. & Joyce, G. F. The effect of cytidine on the structure and function of an RNA ligase ribozyme. RNA 7, 395–404 (2001)
Kirnos, M. D., Khudyakov, I. Y., Alexandrushkina, N. I. & Vanyushin, B. F. 2-Aminoadenine is an adenine substituting for a base in S-2L cyanophage DNA. Nature 270, 369–370 (1977)
Macdonald, L. E., Zhou, Y. & McAllister, W. T. Termination and slippage by bacteriophage T7 RNA polymerase. J. Mol. Biol. 232, 1030–1047 (1993)
Rohatgi, R., Bartel, D. P. & Szostak, J. W. Kinetic and mechanistic analysis of nonenzymatic, template-directed oligoribonucleotide ligation. J. Am. Chem. Soc. 118, 3332–3339 (1996)
Santoro, S. W. & Joyce, G. F. A general purpose RNA-cleaving DNA enzyme. Proc. Natl Acad. Sci. USA 94, 4262–4266 (1997)
Orò, J. Mechanism of synthesis of adenine from hydrogen cyanide under plausible primitive Earth conditions. Nature 191, 1193–1194 (1961)
Sanchez, R. A., Ferris, J. P. & Orgel, L. E. Studies in prebiotic synthesis IV. Conversion of 4-aminoimidazole-5-carbonitrile derivatives to purines. J. Mol. Biol. 38, 121–128 (1968)
Joyce, G. F. Evolutionary chemistry: getting there from here. Science 276, 1658–1659 (1997)
Taylor, S. V., Walter, K. U., Kast, P. & Hilvert, D. Searching sequence space for protein catalysts. Proc. Natl Acad. Sci. USA 98, 10596–10601 (2001)
Plaxco, K. W., Riddle, D. S., Grantcharova, V. & Baker, D. Simplified proteins: minimalist solutions to the ‘protein folding problem’. Curr. Opin. Struct. Biol. 8, 80–85 (1998)
McGinness, K. E., Wright, M. C. & Joyce, G. F. Continuous in vitro evolution of a ribozyme that catalyzes three successive nucleotidyl addition reactions. Chem. Biol. 9, 585–596 (2002)
Acknowledgements
We thank J. Rogers for many discussions during the initial stages of this project. We also thank the members of the Joyce laboratory for their advice and E. Tzima for assistance in preparation of the manuscript. This work was supported by a grant from the National Aeronautics and Space Administration and the Skaggs Institute for Chemical Biology. J.S.R. was supported by a postdoctoral fellowship from the NASA Specialized Center for Research and Training (NSCORT) in Exobiology.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Rights and permissions
About this article
Cite this article
Reader, J., Joyce, G. A ribozyme composed of only two different nucleotides. Nature 420, 841–844 (2002). https://doi.org/10.1038/nature01185
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature01185
This article is cited by
-
Side chain determinants of biopolymer function during selection and replication
Nature Chemical Biology (2019)
-
Six pack and stack
Nature Chemistry (2015)
-
A Metabolic Prototype for Eliminating Tryptophan From The Genetic Code
Scientific Reports (2013)
-
Are Molecular Alphabets Universal Enabling Factors for the Evolution of Complex Life?
Origins of Life and Evolution of Biospheres (2013)
-
Efficient enzyme-free copying of all four nucleobases templated by immobilized RNA
Nature Chemistry (2011)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.