Why do nucleic acids have 3′5′ phosphodiester bonds?

Dhingra, M. M.; Sarma, Ramaswamy H.

doi:10.1038/272798a0

Cited by 54 publications

(25 citation statements)

References 23 publications

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“…Those for A2'-5'U (5.6 mM) are from 360-MHz spectra, those for A2'-5'A (7.4 mM) from 100-MHz spectra It is therefore concluded that the SN stack makes up the far greater part of the stacked state in A2'-5'U at low temperature. This finding is in agreement with NMR studies on A2'-5'C and G2'-5'U [9,32] which revealed a preference for the S conformation in the purine (R) fragment and a preference for the N conformation in the pyrimidine (Y) fragment in R2'-5'Y dinucleotides. The difference between A2'-5'U and A2'-5'A is also seen in the different temperature dependency of the CD spectra.…”

Section: The Conformation Of A2'-5'usupporting

confidence: 81%

“…Second, the A(l) and U(2) ribose rings in the crystal structure of A2'-5'U have the S and N conformation respectively, whereas the interplanar base-base distance equals 0.34 nm. Third, a possible 'mixed' SN conformation is also reflected in the NMR 1 '2'-coupling constants of A2'-5'U, G2'-5'U and A2'-5'C [9,32], This simple statistical 'mixed' stack model cannot be used in the case of A2'-5'A2'-5'A. In this molecule partly stacked states may also be present, e.g.…”

Section: Stackingmentioning

confidence: 99%

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Conformational Analysis of the Nucleotides A2'-5'A, A2'-5'A2'-5'A and A2'-5'U from Nuclear Magnetic Resonance and Circular Dichroism Studies

Doornbos¹,

Hartog²,

Boom³

et al. 1981

Eur J Biochem

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In recent publications A2′‐5′A2′‐5′A was found to be an inhibitor of protein synthesis. In this research conformational analysis of the 2′‐5′‐linked nucleotides A2′‐5′A, A2′‐5′A2′‐5′A and A2′‐5′U is reported. The complete 1H‐NMR assignment of the three compounds is given. The degree and mode of base‐base stacking is extracted from coupling constant data and circular dichroic (CD) spectra at various temperatures. The 2′‐5′ nucleotides surprisingly show a much stronger tendency to stack than the 3′‐5′ compounds. At 85°C A2′‐5′A occurs for about 50% in stacked states. The mode of stacking is different from 3′‐5′ ribonucleotides where the sugar rings predominantly adopt an N conformation. A2′‐5′U displays an A(S)2′‐5′U(N) stacked state. In A2′‐5′A ‘mixed’ modes of stacking, i.e. NN, NS, SN and SS, are proposed to account for the CD and NMR observations.

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Section: The Conformation Of A2'-5'usupporting

confidence: 81%

Section: Stackingmentioning

confidence: 99%

Conformational Analysis of the Nucleotides A2'-5'A, A2'-5'A2'-5'A and A2'-5'U from Nuclear Magnetic Resonance and Circular Dichroism Studies

Doornbos¹,

Hartog²,

Boom³

et al. 1981

Eur J Biochem

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“…2',5"-Linked DNA (21)(22)(23)(24)(25)(26)(27), and there is as well some experimental evidence (28) on the kinetic lability of a normal 3',5" oligonucleotide containing one 2',5" linkage. We have now addressed the properties of two classes of materials: (i) DNA oligonucleotides containing one or two 2',5" linkages in addition to the normal links, and (ii) oligonucleotides with only 2',5" linkages, built up from 3-deoxynucleosides.…”

Section: Cleavage Of Rna By Imidazole and Other Buffersmentioning

confidence: 99%

Recognition and catalysis in nucleic acid chemistry.

Breslow

1993

Proc. Natl. Acad. Sci. U.S.A.

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The enzyme ribonuclease A catalyzes the cleavage ofRNA, using the imidazole groups of histidine-12 and histidine-119 as its principal catalytic groups. Model studies show that RNA can be cleaved by imidazole buffer itself and that, as in the enzyme, a bell-shaped pH vs. rate profile is seen. This indicates that one imidazole functions as a base, while the other, as the imidazolium ion, functions as an acid. However, in contrast to the enzymatic case, the simple model uses the imidazoles in sequential, rather than simultaneous, bifunctional catalysis. Mechanistic studies on this reaction and on the reactions of simple dinucleotides catalyzed by imidazle and other buffers establish the details of the process. The results let us propose a mechanism for the enzymatic process' different from the standard one; they also stimulated us to design an improved mimic of the enzyme that uses a mechanism like that proposed for the enzyme. Critical to the mechanistic studies is observation of the rearrangement of normal 3',5 RNA nudeotides to the 2',5" isomers. This led us to investigate the properties of DNA isomers in which a 2',5" link also replaces the normal 3',5" one. The results indicate that poor base stacking in a double helix with such links makes them less suitable as genetic units.procedure, we were able to show (10) that indeed imidazole buffer catalyzed the cleavage of an RNA, poly(U). As with the enzyme, we saw a bell-shaped pH vs. rate profile for the catalyzed process, with a rate maximum when both imidazole and protonated imidazolium ion were present (Fig. 1). However, it was clear that the two catalysts were not operating simultaneously, in contrast to the likely situation in the enzyme. The reaction was first order in buffer concentration ([buffer]) as shown in Fig. 2 The enzyme ribonuclease A hydrolyzes ribonucleic acid (RNA) by a two-stage mechanism in which first there is ester interchange to form a cyclic phosphate, with cleavage of the chain. Then the 2',3'-cyclic phosphate ester is hydrolyzed by the enzyme. The principal catalytic groups for both the cyclization and the hydrolysis are the imidazole rings of His-12 and His-119, although Lys41 also plays a role. In the classical mechanism seen in most textbooks, the cyclization is catalyzed as the basic imidazole of His-12 deprotonates the 2'-hydroxyl group, while the acidic imidazolium group of protonated His-119 acts to protonate the leaving oxygen atom of the departing nucleoside.Some years ago we initiated a project to investigate the cleavage of RNA by imidazole buffer itself (for a recent review, see ref. 1). If it did catalyze the process, we wanted to learn the detailed mechanism involved. This might well furnish additional insights into the enzyme process, and the preferred mechanism might also be a good guide in the development of artificial ribonuclease enzymes. A number of other studies had been devoted to similar questions, although generally with phenyl esters rather than with the normal leaving group of RNA itself (2-8).We first d...

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“…Although NMR structures of a homogeneously 2′-5′-linked DNA and RNA duplex as well as X-ray crystal structures of 2′-5′-linked dinucleotides have been reported (19)(20)(21)(22)(23)(24)(25)(26), no crystallographic data are available on mixed-backbone RNA. Here we report high-resolution crystal structures of three RNA 10mer duplexes of the same self-complementary sequence, the first being native RNA, the second containing two, and the third containing six 2′-5′ linkages.…”

mentioning

confidence: 99%

Structural insights into the effects of 2′-5′ linkages on the RNA duplex

Sheng

Engelhart

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The mixture of 2′-5′ and 3′-5′ linkages generated during the nonenzymatic replication of RNA has long been regarded as a central problem for the origin of the RNA world. However, we recently observed that both a ribozyme and an RNA aptamer retain considerable functionality in the presence of prebiotically plausible levels of linkage heterogeneity. To better understand the RNA structure and function in the presence of backbone linkage heterogeneity, we obtained high-resolution X-ray crystal structures of a native 10-mer RNA duplex (1.32 Å) and two variants: one containing one 2′-5′ linkage per strand (1.55 Å) and one containing three such linkages per strand (1.20 Å). We found that RNA duplexes adjust their local structures to accommodate the perturbation caused by 2′-5′ linkages, with the flanking nucleotides buffering the disruptive effects of the isomeric linkage and resulting in a minimally altered global structure. Although most 2′-linked sugars were in the expected 2′-endo conformation, some were partially or fully in the 3′-endo conformation, suggesting that the energy difference between these conformations was relatively small. Our structural and molecular dynamic studies also provide insight into the diminished thermal and chemical stability of the duplex state associated with the presence of 2′-5′ linkages. Our results contribute to the view that a low level of 2′-5′ substitution would not have been fatal in an early RNA world and may in contrast have been helpful for both the emergence of nonenzymatic RNA replication and the early evolution of functional RNAs.origin of life | backbone heterogeneity | X-ray crystallography T he capacity of RNA to act as both a carrier of genetic information and as a catalyst has led many to investigate its potential role as the first biopolymer (1-4). An early stage involving nonenzymatic replication simplifies RNA-first scenarios, but known nonenzymatic copying reactions generate a mixture of 3′-5′ and 2′-5′ backbone linkages because of the similar nucleophilicity and orientation of the 2′ and 3′ hydroxyl groups on ribose (Fig. 1). Although regioselectivity for the 3′-5′ linkage can be improved by using different metal ions or activated monomers, it reaches, at most, ∼90% (5-11). This lack of regiospecificity has been regarded as a central problem for the emergence of the RNA world, because the resulting backbone heterogeneity was expected to disrupt the folding, molecular recognition, and catalytic properties of functional RNAs. However, we recently observed that functional nucleic acid molecules can still evolve in the presence of nonheritable mixed DNA/RNA backbone heterogeneity (12), and known functional RNAs retain catalytic and ligand binding behavior in the presence of 2′-5′/3′-5′ backbone linkage heterogeneity (13).The well-known duplex-destabilizing property of 2′-5′ linkages can enable thermal strand separation of long RNA duplexes in the presence of the high Mg 2+ concentrations required for known prebiotic copying reactions (13-16). However, the mechanism r...

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Why do nucleic acids have 3′5′ phosphodiester bonds?

Cited by 54 publications

References 23 publications

Conformational Analysis of the Nucleotides A2'-5'A, A2'-5'A2'-5'A and A2'-5'U from Nuclear Magnetic Resonance and Circular Dichroism Studies

Conformational Analysis of the Nucleotides A2'-5'A, A2'-5'A2'-5'A and A2'-5'U from Nuclear Magnetic Resonance and Circular Dichroism Studies

Recognition and catalysis in nucleic acid chemistry.

Structural insights into the effects of 2′-5′ linkages on the RNA duplex

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