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  • Review Article
  • Published:

The catalytic diversity of RNAs

Nature Reviews Molecular Cell Biology volume 6, pages 399–412 (2005)Cite this article

Key Points

  • Small self-cleaving ribozymes catalyse the same reversible phosphodiester-cleavage reaction, but can adopt different structures and use distinct catalytic strategies. These catalytic RNAs do not require metal-cation cofactors and instead use active-site nucleotide bases for their catalytic chemistry.

  • Structural and biochemical studies of the hepatitis delta virus ribozyme are consistent with models in which an active-site cytosine activates the nucleophile through general base catalysis, whereas a metal-bound water protonates the leaving group. In an alternative model, these roles are reversed and the metal-bound water accepts a proton to activate the nucleophile, whereas cytosine mediates general acid catalysis to stabilize the leaving group.

  • Structural studies of the hairpin ribozyme place two active-site nucleobases near the reactive phosphate where hydrogen-bonding interactions provide electrostatic stabilization to the transition state. The nucleobase that interacts with the bridging 5′ oxygen might also mediate general acid–base catalysis.

  • Biochemical studies support a three-metal model for group-I intron splicing, in which catalytic metal cations activate nucleophiles, stabilize leaving groups and position reactants in the appropriate geometry. Structural studies have so far identified only two active-site metals.

  • The catalytic chemistry that is mediated by ribosomal RNA in the peptidyl-transferase centre of the ribosome focuses on peptide release, whereas the 2′ hydroxyl of the P-site tRNA is important for peptide-bond formation.

Abstract

The natural RNA enzymes catalyse phosphate-group transfer and peptide-bond formation. Initially, metal ions were proposed to supply the chemical versatility that nucleotides lack. In the ensuing decades, structural and mechanistic studies have substantially altered this initial viewpoint. Whereas self-splicing ribozymes clearly rely on essential metal-ion cofactors, self-cleaving ribozymes seem to use nucleotide bases for their catalytic chemistry. Despite the overall differences in chemical features, both RNA and protein enzymes use similar catalytic strategies.

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Figure 1: Hepatitis delta virus ribozyme structure and mechanism.
Figure 2: Hairpin ribozyme structure and mechanism.
Figure 3: Hammerhead ribozyme structure.
Figure 4: Group-I intron catalysis of self-splicing.
Figure 5: The ribosomal catalysis of protein synthesis.

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Acknowledgements

Work in our laboratories is supported by grants from the National Institutes of Health and by the Skaggs Institute for Chemical Biology.

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  1. Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Martha J. Fedor & James R. Williamson

  2. The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Martha J. Fedor & James R. Williamson

  3. Department of Chemistry, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    James R. Williamson

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James Williamson's laboratory

Martha Fedor's laboratory

RNABase.org: The RNA Structure Database

Glossary

RIBOZYME

An enzyme in which RNA functions as the catalytic component.

GROUP-I SELF-SPLICING INTRONS

A group of catalytic RNAs that carry out phosphodiester-cleavage and -ligation reactions, which result in the removal of noncoding intronic sequences and splicing of coding exon sequences. Group-I introns were the first class of catalytic RNAs to be discovered.

SN2-TYPE IN-LINE MECHANISM

The chemical term for a class of nucleophilic substitution reactions that involve a concerted attack of a nucleophile and the departure of a leaving group.

TRANSITION-STATE THEORY

A general chemical theory whereby the trajectory of a chemical reaction proceeds from the starting reagents through a high-energy, short-lived transition state towards the products.

GENERAL ACID OR BASE

A proton acceptor or a proton donor that is not the solvent.

IMIDAZOLE

A small heterocyclic compound that contains two nitrogen atoms in a five-membered ring. Imidazole has chemical groups that can serve as a general acid or a general base in catalysis. The amino acid histidine has an imidazole group as its side chain.

LEWIS ACID

Any functional group or chemical that can interact with unpaired electrons.

pH-RATE PROFILE

The measurement of a reaction rate as a function of varying pH values, which can be an indicator of the presence of acid or base catalysis.

KINETIC EQUIVALENCE

The principle that underlies the fact that it is often not possible to determine if either acid- or base-catalytic mechanisms are operative from the pH dependence of a reaction rate. This is because different reaction mechanisms can give rise to identical pH-rate profiles that reflect different, but kinetically equivalent, rate equations.

ROLLING-CIRCLE REPLICATION

A replication mechanism commonly used by virus-associated RNAs, whereby a circular DNA or RNA template is continuously replicated around a circle to make a concatenated linear polymer of genomic copies. Self-cleaving ribozymes are often responsible for the cleavage of monomeric genomic RNAs from the linear polymeric strand, and for the rejoining of the monomeric RNA termini to form circular templates for subsequent rounds of replication.

PLANT SATELLITE RNA

An RNA that is associated with plant viruses and that does not itself contain any functional open reading frames.

ABASIC

Lacking a nucleotide base, which can occur, for example, when a nucleotide is substituted with a linker that maintains the ribose–phosphate backbone but has a hydrogen atom in place of the nucleotide base.

PURINE

An aromatic, heterocyclic base that consists of a six-membered pyrimidine ring fused to a five-membered imidazole. Adenine and guanine are the most common purines that are joined to ribose in the ribonucleotide building blocks of RNA.

PYRIMIDINE

An aromatic, heterocyclic base that contains two nitrogen atoms in a six-membered ring. Uracil and cytosine are the most common pyrimidines that are joined to ribose in the ribonucleotide building blocks of RNA.

THIOPHILIC

Attracted to sulphur.

SPECIFIC ACID OR BASE

Solvent acid or base species, which, for water, are H+ and OH−.

PRO-RP AND PRO-SP

The chemical terms that specify the two stereochemically distinct nonbridging oxygen atoms of a phosphodiester.

P SITE

The site in the peptidyl-transferase centre of the ribosome that binds to the tRNA that is attached to the growing peptide chain.

PUROMYCIN

An antibiotic compound that inhibits protein synthesis and that binds to the ribosome as an analogue of aminoacyl-tRNA.

A SITE

The site in the peptidyl-transferase centre of the ribosome that binds the incoming aminoacyl-tRNA.

ZWITTERION

A dipolar ion that contains ionic groups of opposite charge, and has a net charge of zero.

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Fedor, M., Williamson, J. The catalytic diversity of RNAs. Nat Rev Mol Cell Biol 6, 399–412 (2005). https://doi.org/10.1038/nrm1647

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