Ribozymes and RNA Catalysis (RSC Biomolecular Sciences)

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Change Language. Contemporary ribozymes Table 1. The nucleolytic ribozymes bring about the site-specific cleavage or the reverse ligation process of RNA by attack of a hydroxyl group on the adjacent phosphorus Figure 1. This reaction is exploited for the processing of replication intermediates, and in the control of gene expression by metabolite-induced cleavage of mRNA.

Ribonuclease P carries out the processing of tRNA in all kingdoms of life, using a hydrolytic reaction Chapter 9. Several introns are spliced out autocatalytically by ribozyme action, initiated either by the attack of a hydroxyl group located remotely within the intron group II introns, Figure 1. Lastly, the peptidyl transferase activity of the ribosome catalyses what is arguably the most important reaction of the cell, the condensation of amino acids into polypeptides Chapter Ribozymes are widespread in nature, from bacteria and their phages, archaea, yeasts and fungi and higher eukaryotes.

They are also present in clinically-significant human pathogens such as the hepatitis D virus Chapter 6.

Ribozyme structure and activity..........................

New ribozymes are still being found, both by biochemical approaches and by the bioinformatic analysis of genome sequencing data. Protein enzymes can achieve some extraordinary catalytic rate enhancements. Values of almost fold are possible, although many generate much smaller accelerations. RNA catalysts tend to produce more modest rate enhancements. For example, the nucleolytic ribozymes typically accelerate their transesterification reactions by around a million-fold relative to the uncatalysed reaction in a dinucleotide, with rates of around 1 min For those ribozymes this may be as fast as it needs to be, since a given site needs to be cut just once.

There are several reasons for studying ribozymes. First, they are active in contemporary living cells, carrying out reactions that are critical for cell viability in some cases; they are therefore legitimate subjects of interest in the complete description of cellular metabolism. Second, they may have had a key role in the evolution of life on the planet.

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There is clearly a rather severe "chicken and egg" problem involved in the origins of proteins and translation systems, both of which seem to require the prior existence of the other. Yet in principle a biosphere in which RNA was simultaneously the informational and catalytic macromolecule provides a temporary solution to that problem. Such an RNA world might have existed around 3. Some of the ribozymes that currently exist, most notably the ribosome perhaps, may be molecular fossils from that time, and therefore their study may offer a partial glimpse of that early metabolism.

Although contemporary ribozymes carry out a very limited range of chemistries, selected ribozymes provide an indication of what is achievable by RNA catalysts, and potentially offer a kind of proof-of-principle of an RNA world. A third reason for studying ribozymes is that they are rather basic biocatalysts, providing a simplified and contrasting perspective on macromolecular catalytic mechanisms compared with enzymes.

The last few years have seen significant advances in our understanding of the chemical origins of ribozyme catalysis, and this may cast light on protein-based catalysis in turn. Lastly, there has been some effort to exploit the potential specificity of ribozymes as therapeutic agents. In principle, the great selectivity of ribozyme-induced cleavage of a chosen sequence could provide an opportunity to interfere with gene expression if targeted to a specific mRNA; this should ideally be the basis for their development into therapeutic drugs.

However, this requires that many more problems be overcome, including stability in serum, delivery to the required location of the chosen cell and correct folding into the active conformation in competition with the native folding of the target RNA in vivo.

Ribozymes and RNA Catalysis

So far only two ribozymes have found their way into clinical trials. In preclinical trials it has exhibited antitumor and antimetastatic activity by interfering with VEGF-dependent angiogenesis. Angiogenesis inhibition is important in patients with refractory solid tumours. The other example involved the use of a hammerhead ribozyme as part of a vector to combat HIV The ribozyme directs the cleavage of the transcript of the chemokine receptor CCR5 that is essential for HIV-1 infection.

Potent inhibition of HIV-1 replication was achieved with this construct in a human T cell line. Just as protein enzymes must be correctly folded into the conformation required for catalytic activity, so must RNA. Moreover, it is clear that the folding processes of ribozymes is intimately associated with their function in many cases. Marked differences between the chemical nature of RNA and proteins results in very different folding processes. In general the precise nature of Watson—Crick basepairing leads to the relatively easy formation of secondary structure, although a requirement to "un-do" unfavourable pairings can provide significant barriers to correct folding.

But most of the attention in RNA folding is focussed on the formation of the tertiary structure. The polyelectrolyte character of RNA results in a strong electrostatic contribution to this process, and thus a dependence on the presence of metal ions. The resulting folded RNA structure can bind metal ions, either site-specifically or diffusely, and these bound ions can play a direct role in catalysis. Site-bound ions are inner-sphere complexes where one of more water molecules in the first coordination sphere have exchanged with ligands provided by the RNA; such ions exchange slowly with bulk solvent.

Diffusely bound ions do not undergo ligand substitution, and consequently exchange with solvent much more rapidly. They can nevertheless exhibit high occupancy in sites of strong electrostatic potential. The smaller ribozymes, notably the nucleolytic ribozymes, exhibit some common structural themes, and their architectures are based around either helical junctions hammerhead, hairpin and VS or pseudoknots HDV, glmS ; evidently these motifs are efficient ways to construct small, autonomously folding species.

Furthermore, some of these ribozymes contain additional elements that are not strictly essential for catalytic activity, yet result in marked enhancement of folding, such as the interacting loops of the hammerhead and the four-way junction of the hairpin ribozyme.

Ribozymes and RNA Catalysis (RSC Biomolecular Sciences)

Most studies of RNA folding in vitro have therefore focussed on ion-induced folding. The small nucleolytic ribozymes generally exhibit relatively simple folding, typically two or three-state processes. However, larger ribozymes like the group I introns undergo complex folding pathways, beset with kinetic traps Chapter In the cell, proteins may assist the folding processes. The chemical nature of proteins has evolved to provide a highly adaptable catalytic framework with a broad repertoire of functional groups. It is based on an electrically neutral backbone, with sidechains that introduce a wide variety of chemistries, including carboxylic acids, amines, hydroxyl and thiol groups as well as hydrophobic side chains that may be either aliphatic or aromatic.

By contrast, RNA consists of just four nucleotide bases of rather similar chemical nature, connected by an electrically-charged ribose-phosphate backbone. So what resources are available to RNA that can be used to build a catalyst?

Firstly, there are the nucleobases.