Thus enzymes speed up reactions by lowering activation energy. Many enzymes change shape when substrates bind. This is termed "induced fit", meaning that the precise orientation of the enzyme required for catalytic activity can be induced by the binding of the substrate.
A major question remains, however: What are these molecules and where do they come from? What other molecules in the cell provide enzymatic regulation, such as allosteric modulation, and competitive and noncompetitive inhibition? The answer is that a wide variety of molecules can perform these roles.
Some of these molecules include pharmaceutical and non-pharmaceutical drugs, toxins, and poisons from the environment. Perhaps the most relevant sources of enzyme regulatory molecules, with respect to cellular metabolism, are the products of the cellular metabolic reactions themselves. In a most efficient and elegant way, cells have evolved to use the products of their own reactions for feedback inhibition of enzyme activity.
The cell responds to the abundance of specific products by slowing down production during anabolic or catabolic reactions. Such reaction products may inhibit the enzymes that catalyzed their production through the mechanisms described above. The production of both amino acids and nucleotides is controlled through feedback inhibition.
Additionally, ATP is an allosteric regulator of some of the enzymes involved in the catabolic breakdown of sugar, the process that produces ATP. In this way, when ATP is abundant, the cell can prevent its further production.
If too much ATP were present in a cell, much of it would go to waste. On the other hand, ADP serves as a positive allosteric regulator an allosteric activator for some of the same enzymes that are inhibited by ATP. Enzymes are chemical catalysts that accelerate chemical reactions at physiological temperatures by lowering their activation energy.
Enzymes are usually proteins consisting of one or more polypeptide chains. Enzymes have an active site that provides a unique chemical environment, made up of certain amino acid R groups residues.
This unique environment is perfectly suited to convert particular chemical reactants for that enzyme, called substrates, into unstable intermediates called transition states. Enzymes and substrates are thought to bind with an induced fit, which means that enzymes undergo slight conformational adjustments upon substrate contact, leading to full, optimal binding.
Enzymes bind to substrates and catalyze reactions in four different ways: bringing substrates together in an optimal orientation, compromising the bond structures of substrates so that bonds can be more easily broken, providing optimal environmental conditions for a reaction to occur, or participating directly in their chemical reaction by forming transient covalent bonds with the substrates.
Enzyme action must be regulated so that in a given cell at a given time, the desired reactions are being catalyzed and the undesired reactions are not. Enzymes are regulated by cellular conditions, such as temperature and pH. They are also regulated through their location within a cell, sometimes being compartmentalized so that they can only catalyze reactions under certain circumstances. Inhibition and activation of enzymes via other molecules are other important ways that enzymes are regulated.
Inhibitors can act competitively, noncompetitively, or allosterically; noncompetitive inhibitors are usually allosteric. Activators can also enhance the function of enzymes allosterically. The most common method by which cells regulate the enzymes in metabolic pathways is through feedback inhibition.
During feedback inhibition, the products of a metabolic pathway serve as inhibitors usually allosteric of one or more of the enzymes usually the first committed enzyme of the pathway involved in the pathway that produces them. Skills to Develop Describe the role of enzymes in metabolic pathways Explain how enzymes function as molecular catalysts Discuss enzyme regulation by various factors.
Link to Learning View an animation of induced fit at this website. Active site of T. Copyright Nature Press. Figure 9. Hepatitis delta virus.
A Secondary structure of the trans-acting HDV ribozyme used for crystallography. B Line representation of the crystal structure demonstrating a partially hydrated magnesium ion coordinated to the active site. Copyright American Chemical Society. Figure HDV ribozyme active site with a modeled hammerhead scissile phosphate substrate. The HDV structure at 1. In pink are the nucleotides immediately surrounding the scissile phosphate from a structure of the hammerhead ribozyme, built into the HDV structure using G1 for alignment.
C75 is shown within hydrogen-bonding distance of the leaving group, consistent with a role as the general acid in this reaction. Proposed mechanism for HDV ribozyme catalysis. In the presence of divalent metal ions, the reaction is proposed to be concerted and to pass through a phosphorane-like transition state ref Structure and active site of the hammerhead ribozyme. Structure 2OEU of the S. Biochemical studies predict that the metal ion contacts P1.
Hairpin ribozyme active site. A Reaction catalyzed by the HP ribozyme and proposed contributions of A38 as a general acid and G8 in hydrogen-bond interactions. C Close-up of the 2OUE active site.
The G8 N6 forms a hydrogen bond with the scissile phosphate. D Close-up of a transition-state analogue 2P7F.
In this structure, A38 N1 is repositioned to act as proton donor to the leaving group. An elevated p K a of 6. Varkud satellite VS ribozyme. Tertiary structure model of the VS ribozyme based on biophysical measurements. Experimental pH-rate profiles for the VS C and hairpin F ribozymes and theoretical curves demonstrating the effects of changing magnitude A,D,E and identities A,B of predicted general acid and base values.
Both ribozymes are proposed to have conserved A and G nucleobases that could act as general acid and general base, respectively. Their pH-rate profiles differ significantly, however, indicating different nucleobase roles and the possible modulating influence of a metal ion in the case of the VS ribozyme. Theoretical curves show the influence of changing pKa values on resultant active ribozyme populations. Structure and active site of the GlmS metabolite-sensing ribozyme.
A,B GlcN6P binds to a cleft in a preformed RNA structure such that C its amine can activate ribozyme activity through protonation of the leaving group. Copyright AAAS. Selection of the Diels—Alderase ribozyme. A biotinylated maleimide was reacted with an anthracine linked to a randomized pool of RNA flanked by priming regions.
The products of the reaction resulted in a covalent linkage between the RNA pool and the biotin tag, which was used to separate candidate catalytic RNA sequences. Copyright Elsevier. Structure of the Diels—Alderase ribozyme. Mg1 and Mg2, arguably the most important metal ions for maintaining catalytic activity, are shown as red spheres.
In green are the three nucleotides involved in important hydrogen bonding, G9, C10, and U Electronic fine-tuning in the Diels—Alderase ribozyme active site. Two nucleotides G9 and U17, green form hydrogen bonds with one of the carbonyl oxygens of the reaction product gray. The carbonyl oxygen arises from the dienophile in the Diels—Alder reaction. DNAzymes that cleave an embedded ribonucleotide site vertical arrow.
Below, single turnover rate constants of the 17E DNAzyme in the presence of different divalent metal ions at pH 6. Spider with DNAzyme legs that moves on a surface patterned with substrate oligonucleotides. A DNAzyme spider leg binds and cleaves substrate and is then released from the lower-affinity product helix to reanneal to the next substrate strand.
At right, the spider moves through a pattern of low-affinity product light brown toward high-affinity substrate dark brown strands, stopping at a noncleavable all-deoxy stop red oligonucleotide. He did his doctoral research in the DeRose laboratory at the University of Oregon and received his Ph. He is currently working as a postdoctoral researcher in the Russell laboratory at the University of Texas at Austin. Generally interested in RNA structural biology, he is currently focusing on single-molecule characterization of RNA chaperone activity.
Kory Plakos received his B. Kory is currently working toward his Ph. He is generally interested in high-throughput structure determination of complex RNAs, with a focus on structure—function relationships. She was promoted to Associate Professor in , and in , she moved to the University of Oregon.
She is generally interested in the interface of chemistry and biology, with an emphasis on bioinorganic and biophysical properties of proteins and nucleic acids. We thank members of the DeRose laboratory for helpful discussions. View Author Information. Cite this: Chem. ACS AuthorChoice. Article Views Altmetric -. Citations The discovery of RNA-catalyzed phosphodiester bond cleavage by Cech and Altman in — shattered the paradigm of protein-dependent biological catalysis and opened up new horizons for RNA biology reviewed in ref 1.
These discoveries ushered in a new era of high activity in RNA biochemistry and structural biology that, in conjunction with developments in genomics, established groundwork for the ensuing explosion in discoveries of other functional but noncoding RNAs. Since the initial discoveries, several classes of naturally occurring and artificially developed ribozymes have been defined. Ribozyme reactions catalyzed in nature include phosphoryl and aminoacyl transfer reactions Figure 1.
RNA-catalyzed reactions obtained in vitro extend to carbon—carbon bond formation in the Diels—Alderase ribozyme. In vitro selection has also been employed to discover DNA-based enzymes that catalyze a number of different reactions, including RNA cleavage, as in Figure 1 A. High Resolution Image. As with metalloproteins, the active sites of several ribozymes include site-specific metal-ion cofactors whose properties influence chemical reactivity.
The bioinorganic chemistry of RNA differs significantly from that of proteins, however. Unlike metalloproteins, the naturally occurring ribozymes discovered so far do not catalyze redox reactions.
It should be noted that transition metals certainly bind to RNAs and might have regulatory 3 or early biotic 4 roles, and in some cases, they can support high activity in ribozymes, but evidence for transition-metal-supported ribozyme activity in vivo is not established.
In addition, unlike in the case of most proteins, the influence of inorganic cations on RNA structure, particularly tertiary structure, is very strong. RNA is a negatively charged biopolymer, carrying one charge per phosphodiester bond. The four nucleobases are expected to be neutral except in rare cases. A major challenge for mechanistic and structural studies in ribozymes has been separating the influence of metal-ion cofactors on structure from their influence on chemical reactivity.
Since the discovery of ribozymes, the central quest has been to understand how the relatively limited chemical functionalities of oligonucleotides are able to catalyze reactions with nearly the same efficiency and selectivity as proteins.
The main focus of this review is metal-ion-assisted catalysis in ribozyme mechanisms. Two classes of phosphoryl-transfer-catalyzing ribozymes are discussed in this review. We do not review the active site of the ribosome. Although the ribosome-catalyzed reaction is clearly an RNA-dependent reaction governed by an intricate RNA active site, specific roles for metal ions are not evident in this reaction, and it has been recently reviewed.
Neither of these ribozymes have specific metal-ion cofactors, but their active sites provide demonstrations of the other roles contributed by RNA moieties in catalyzing reactions. This topic is also briefly reviewed to acquaint the reader with that field. Included in this review is also a brief overview of methods applied to studies of ribozymes, as some aspects of this field differ from similar activities in protein enzymology.
Several other reviews of ribozymes have appeared in the past 10 years. Recent reviews on RNA—metal or RNA—ion-atmosphere interactions have focused on thermodynamics, 15 detection by biochemical, 16 spectroscopic, 17, 18 or X-ray scattering 19 methods, and metal-coordination properties of nucleic acids.
Ribozymes, like other enzymes, use a variety of strategies to lower the energetic barriers of chemical reactions. The active site can also position functional groups from the substrate, enzyme, solvent, and cofactors to assist catalysis.
Electronic properties of functional groups, manifested as shifts in nucleophilicity or p K a , might be tuned by the electrostatic environment of the active site.
Typically, an active site is protected from bulk solvent. Although these are common and well-studied strategies for proteinaceous enzymes, there are particularly challenging aspects about the nature of ribonucleic acids that ribozymes must overcome to efficiently organize an active site and catalyze chemical reactions. The most obvious difference between RNA and proteins, and seemingly greatest challenge to RNA and DNA chemistry in general, is the lack of chemical diversity provided by the four standard nucleobases Figure 2 in comparison with 20 common amino acids.
Nucleobases afford amino and imino nitrogen groups with p K a values above 9 or below 4, but not the near-neutral p K a of the histidine imidazole. The keto oxygens of nucleobases provide hydrogen-bond donor groups and electrostatic tuning, but there are no carboxylic acids for proton shuttles or metal chelation.
Given these limitations, the fact that RNA sequences can encode enough structural diversity to create active sites, to selectively bind small molecules and cofactors, and to tune the properties of these groups for chemical reactivity is fairly amazing.
One advantage is found in the varieties of secondary and tertiary elements, such as helices, loops, bulges, and base triples, that allow RNA to fold into complex structures that enable the formation of intricate active sites.
Metal-ion interactions with RNA, a negatively charged polyelectrolyte, range from general charge shielding to highly specific coordination sites. Cations nonspecifically condense around the negative charge of the phosphodiester backbone, resulting in a mobile counterion atmosphere that provides general charge shielding.
Although monovalent cations can fulfill this role, the charge density of divalent metals can add stability in regions where several phosphates come within close proximity, such as in RNA turns or helical junctions. RNAs also create specific sites for metal-ion association that are important to structure and function.
Electron-rich groups e. In some cases, a metal ion can coordinate two or more groups from separate secondary structural motifs, thereby bridging domains and stabilizing a specific tertiary structure. In addition to providing ribozymes with structural stability, metal ions can play key roles in catalysis Figure 3. Moreover, a bound metal could potentially organize a water molecule for general acid catalysis. Inner-sphere coordination might also play important roles in ribozymes.
For instance, coordination by a metal to a phosphate oxygen in the ground state increases the electrophilicity of the phosphorus by withdrawing electron density. Further, coordination to a phosphate oxygen can stabilize the negative charge accumulation of the proposed trigonal-bipyramidal phosphorane transition state of phosphoryl-transfer reactions. These types of active-site inner-sphere coordination modes are observed in the group I and group II introns and potentially in the hammerhead ribozyme vide infra.
Metal ions can also influence reactions without interacting directly with catalytic functional groups. Coordination of metal ions to nucleobases withdraws electron density, thereby affecting the p K a values of other substituents in the ring. Both the hairpin ribozyme and the ribosome are thought to promote catalysis without utilizing a catalytic metal. However, divalent metals are still important for folding of these RNAs and, therefore, could aid in defining the electrostatics of the active site and provide other long-range effects.
Ribozymes and other functional noncoding RNA systems are frequently studied as subdomains that represent truncated sequences isolated from their natural context. Much as membrane proteins are sometimes truncated to form soluble domains, these RNAs form discrete folded structures and are designed to maintain the activity of interest. As with truncated proteins, however, it is helpful for the reader to keep the natural context in mind.
In addition, the smaller nucleolytic ribozymes such as the hammerhead and hairpin ribozymes are often studied as truncated constructs that represent the minimal catalytic unit. For mechanistic studies, these, and the hepatitis delta virus and other ribozymes, have also usually been redesigned from natural cis-cleaving systems to RNAs that cleave a substrate in trans conformation.
The re-engineering of naturally occurring ribozymes has enabled great insights into the fundamentals of RNA catalysis. In the case of the hammerhead and hairpin ribozymes, early truncated constructs are acknowledged to have lost tertiary interactions that aid in folding, thereby obfuscating the individual contributions of metal ions to folding and catalysis; later constructs reinstated these properties. Several function-based biochemical approaches have been developed to help identify and isolate the roles of metal ions in RNA catalysis.
Because RNA requires cations to fold, it is generally impossible to do a deletion experiment that entirely removes active-site electrostatic contributors. On the other hand, a popular approach has been to compare the effect of cation identity on the rate of ribozyme catalysis.
However, for cases such as the hammerhead, hairpin, and GlmS ribozymes for which very high concentrations of monovalent cations can support varying levels of ribozyme activity, it has also been found that conserved nucleobases play intimate roles in the reaction. Taken together, these observations indicate that such ribozymes have multiple types of groups that contribute to the catalytic center, allowing function to be supported by cations with a variety of properties.
In the case of the hairpin and GlmS ribozymes, all current evidence indicates that cations do not directly contact active-site groups, although nearby structural metal ions might exert an electrostatic influence. By contrast, the large group I, group II, and RNase P ribozymes are not active in high molar concentrations of monovalent cations and have a distinct requirement for divalent cations. A powerful method for probing possible inner-sphere coordination sites is to create substitutions of functional groups that introduce biochemical and spectroscopic specificity.
These substitutions, however, are not sterically equivalent to oxygen, and therefore, a different ionic radius can perturb an active site and potentially affect catalysis without showing rescue. Thus, although observation of metal rescue might be a good predictor of a specific metal-ion site, the absence of rescue does not necessarily exclude relevant inner-sphere coordination.
The phosphorothioate substitution also provides a marker for 31 P nuclear magnetic resonance NMR studies, because the sulfur atom induces a 50—60 ppm downfield shift in the 31 P signal from the substituted site. Other spectroscopic techniques, including proton NMR, electron paramagnetic resonance EPR , and X-ray absorption spectroscopies can in some cases be used for more direct observation of metal-ion associations with RNA in solution reviewed in refs 17 and Identifying metal ions and their ligands by X-ray crystallography is a powerful but difficult business in complex RNAs.
As has been noted, 3 data interpretation regarding metal sites is aided by high resolution, which is less available for RNA structures than for proteins given the dynamic nature of the RNA backbone. Metal-ion substitution, preferably with anomalous scattering, is a gold standard for metal-site identification by X-ray crystallography.
Given sufficient resolution to obtain distances and geometries, whether a particular metal is making contact with surrounding ligands through inner-sphere or outer-sphere contacts can be inferred. Ribozymes must often be designed to incorporate debilitating substitutions to facilitate crystallization and, therefore, might lose interactions needed to properly position the active site.
Local RNA structure is often based on networks of interactions and can be quite sensitive to changes in hydrogen bonding and other substitutions.
Thus, as is the case with protein enzymes but perhaps even more so with ribozymes, the compelling information gained from X-ray crystallography must be carefully analyzed with respect to corresponding biochemical data. Computational approaches have the potential to deepen understanding of reaction pathways and the contributions that have been evolved in RNA that direct specific reactions. Great progress has been made in recent years, and the field is developing its own version of the blind CASP computer-aided structure prediction challenge for RNA structure prediction.
Because of the challenges noted above in X-ray structure analysis and theoretical modeling of RNA properties, there is great emphasis on coupling theoretical approaches closely with experimental predictions and verification.
In the subsequent sections, current mechanistic proposals for the majority of naturally occurring ribozymes are presented. Figure 4 provides a composite summary of the ground-state active sites for six of these catalysts. These three ribozymes in general occur as large RNAs of several hundred nucleotides and, in the case of the group I and II introns, catalyze two separate reactions in the act of splicing.
The hairpin and Neurospora VS ribozymes appear to use similar nucleobases in their active sites, but the pH-dependent behaviors of their reactions differ, posing an unresolved mystery for these catalysts. Finally, we include an in vitro evolved ribozyme, the Diels—Alderase, as an example of the breadth of reactions available in RNA catalysis, and conclude with DNA catalysts.
The phosphoryl transfer in the second step ligates the two exons in essentially the reverse reaction of the first step and is depicted in Figures 4 and 5. Both reaction steps are proposed to be catalyzed by one active site that is dominantly organized by the intron itself and includes the guanosine binding pocket and conserved metal-ion sites.
Over the ca. Combined with recent structural data, current models of the group I active site reveal a series of phosphate—metal inner-sphere interactions that elegantly organize the ribozyme core through several multidentate metals.
From biochemical studies, a working model of the group I catalytic site has long included three metal ions that are predicted to influence the nucleophile, substrate, and leaving group. For clarity, we have combined the two naming schemes that have been used to distinguish individual metals in the group I intron active site, such that the specificier from crystallography 1 or 2 is followed by that used from metal rescue experiments A, B, or C.
Several crystal structures of group I introns have been reported, and although most are of the group I intron found in the anticodon loop of pre-tRNA Ile in the purple bacterium Azoarcus , there are also structures from pre-rRNA in the ciliate Tetrahymena and bacteriophage Twort.
Initial structure reports differed, however, in the metal-ion content around the active site of the intron. It is not possible, however, to easily place an additional metal M B into the current structures without requiring some structural rearrangement.
With M B modeled into the 3. In evaluating the relationship between group I intron crystal structures and models from biochemical analyses, it is important to note that each experimental system samples different steps in the reaction pathway. Both splicing reactions can take place using an active site that is largely conserved, but some structural rearrangements to accommodate different substrates are certainly possible. Most biochemical assays use a group I intron ribozyme that models the first step of the reaction.
The prediction of three separate catalytic metal ions is based on a series of metal-specificity experiments, in which one or a subset of potential metal-ion ligands in the ribozyme core are substituted to alter their metal-ion preferences.
The X-ray structures, by contrast, are of ribozymes either without exogenous substrates or monitoring steps in the second reaction. Overall, the current high level of information concerning the group I intron active site highlights the importance of combining results from multiple approaches and constructs in RNA structure—function analysis.
The group II introns are the second largest of the naturally occurring ribozymes and are an extremely diverse family with a strong relationship to the eukaryotic splicing machinery. In vivo, group II introns often have protein cofactors, and only a subset depend solely on RNA for efficient catalysis. Like the group I introns, the group II introns are class I ribozymes, catalyzing two consecutive phosphoryl-transfer reactions between nonadjacent nucleotides.
Both phosphoryl-transfer reactions are highly reversible, and the intron can be designed to target any sequence. Group II introns have the additional ability to use DNA as a natural substrate for the reverse reaction.
Group II introns have a generally conserved secondary structure with highly conserved core elements, the most significant being the D5 helix. Although the group II introns have a strict requirement for divalent metals for activity, the family is so diverse that optimal cation concentrations for in vitro activity have been found to range between 0.
Several metal-rescue experiments have been performed on the Saccharomyces cerevisiae aI5 gamma intron to determine the function of metal ligands within the active site. Interactions of metals with the attacking nucleophile were also investigated for the second step of splicing.
These experiments again used sulfur substitution, but they monitored the reverse reaction because sulfur is a poor nucleophile for a phosphorus center. A crystal structure of a group II intron from the halotolerant bacterium Oceanobacillus iheyensis at 3. This reaction step is chemically more similar to the group I reactions, and indeed, the metal ions are positioned solely by bridging and terminal phosphodiester ligands in a manner nearly identical to that observed for group I.
Further crystallographic analysis of O. This study, through a set of 14 different structures solved with various cations, anomalous scattering, and different substrates, provides a thorough working model for group II intron catalysis.
In vivo, the holoenzyme contains an RNA subunit and one or more protein subunits. Also, unlike other naturally occurring nucleolytic ribozymes that catalyze reversible but single intrastrand cleavage reactions, RNase P catalyzes multiple turnovers in nature and, therefore, can be considered a true enzyme.
Protein-only RNase P molecules have only recently been discovered in a handful of systems, including human mitochondria and plants. The diversity of PRNA sequences along with differences in protein cofactors and substrate specificities creates a complex picture of the enzyme in terms of folding, substrate docking, and activity.
Simplifying the situation, a majority of biochemical and structural studies have been performed on bacterial RNase P, which has only one protein cofactor. Recently reported structures of PRNA from Thermatoga maritima 62 Figure 7 and Bacillus stearothermophilus 63 show strong similarities in the overall RNA fold from these two different classes, as predicted by previous studies.
These structures have been used in combination with biochemical, phylogenetic, and computational analyses to provide theoretical models for the RNase P holoenzyme with bound substrate, predicting that the protein cofactor approaches the active site and makes contacts that help position the substrate tRNA.
Not surprisingly, then, although PRNA alone can be catalytic, addition of the protein changes properties such as substrate binding and requirements for metal ions. Certain characteristics of the reaction that relate to the mechanism, such as pH dependence and sensitivity to active-site phosphorothioate substitutions, remain generally the same with and without the protein cofactor, indicating that the same basic mechanism is used in reactions catalyzed by RNA-only and holoenzyme RNase P.
RNase P RNA has been shown to be dependent on divalent metals for correct folding, substrate recognition, and catalysis. As with all ribozymes, picking out the specific contributions of individual ions to catalysis is quite a challenge. The activity and folding of PRNA in several divalent metal combinations suggests that there are both structural and catalytic requirements. At this time, there is positive evidence for direct metal-ion contacts with a nonbridging oxygen of the pre-tRNA scissile phosphate and for a metal hydroxide as the attacking nucleophile Figure 8 d.
Rescue experiments using sulfur substitutions in the scissile phosphate of precursor tRNA substrates indicate an inner-sphere coordination to the pro - R nonbridging oxygen. A recent set of X-ray structures of bacterial T. Although these structures have insufficient resolution, at 3. The available biochemical and structural evidence suggests, however, an active site in which at least one metal ion binds to the scissile phosphodiester bond and also delivers the hydroxide nucleophile for pre-tRNA cleavage.
Despite great progress in understanding RNase P, much work remains to be done on this highly conserved system. The hepatitis delta virus HDV ribozyme Figure 9 is a class II ribozyme, and like the hairpin ribozyme, it is present in circular subviral RNAs for processing genomic units during rolling circle replication. For example, the HDV-like CPEB3 ribozyme, first discovered through an in vitro selection method in the human genome, has been shown to be highly conserved in mammals.
Numerous HDV ribozyme crystal structures have been solved. The first structure was solved in and depicted the ribozyme in a postcleavage state. Occlusion of the active site allows rigidity and structural organization, and the HDV ribozyme has comparatively higher catalytic rates than other class II ribozymes. The early HDV structure supported later biochemical results regarding the catalytic mechanism. In this structure, the N3 of cytosine 75 is positioned to act as a general acid for activation of the leaving group.
This hypothesis is supported by the discovery that the p K a of C75 is shifted near neutral 88 and a C75U mutation is deleterious to ribozyme catalysis. A metal ion is not observed in the active site of the structure, which is surprising because the HDV ribozyme utilizes a nonspecific divalent metal ion for catalysis.
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