Influence of substituents at the 5 position on the structure of uridine

Egert, Ernst; Lindner, H. J.; Hillen, Wolfgang; Boehm, Michael C.

doi:10.1021/ja00531a007

Cited by 43 publications

(26 citation statements)

References 7 publications

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“…This enhancement corresponds to about a 0.4 kcal/mol free energy difference (according to the Boltzmann distribution), which does cause an excess of north pucker in monomer simulations. However, this discrepancy does not occur for unmodified uridine, which uses NA36 parameters, while most modified uridines, especially in the anticodon, are known to stabilize the north ( C3'endo ) conformation . The one exception, dihydrouridine (discussed below), does not use this set of χ parameters.…”

Section: Resultsmentioning

confidence: 99%

Additive CHARMM force field for naturally occurring modified ribonucleotides

Vanommeslaeghe

Aleksandrov

et al. 2016

J Comput Chem

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More than 100 naturally occurring modified nucleotides have been found in RNA molecules, in particular in tRNAs. We have determined molecular mechanics force field parameters compatible with the CHARMM36 all-atom additive force field for all these modifications using the CHARMM force field parametrization strategy. Emphasis was placed on fine tuning of the partial atomic charges and torsion angle parameters. Quantum mechanics calculations on model compounds provided the initial set of target data, and extensive molecular dynamics simulations of nucleotides and oligonucleotides in aqueous solutions were used for further refinement against experimental data. The presented parameters will allow for computational studies of wide range of RNAs containing modified nucleotides including the ribosome and transfer RNAs.

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Section: Resultsmentioning

confidence: 99%

Additive CHARMM force field for naturally occurring modified ribonucleotides

Vanommeslaeghe

Aleksandrov

et al. 2016

J Comput Chem

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“…76% of the S-conformers; the conformation of the bromo and iodo derivatives 1b,c are shifted towards N (72 and 73% S). These data demonstrate that the higher the electron-withdrawing effect of the 7-substituent is, the more the N > S equilibrium of the sugar moiety is biased towards the N-conformation [23] [24]. Table 3 compares the data with a series of other 7-halogenated 7-deazapurine nucleosides 1a ± c related to dA, dG, and dI [6 ± 9] [25] [26], i.e., 6a ± c, 7a ± c, and 8a ± c, which show the same phenomenon.…”

mentioning

confidence: 76%

7‐Halogenated 7‐Deaza‐2′‐deoxyxanthine 2′‐Deoxyribonucleosides

Seela

Shaikh

2004

Helvetica Chimica Acta

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The synthesis of the 7-halogenated derivatives 1b (7-bromo) and 1c (7-iodo) of 7-deaza-2'-deoxyxanthosine (1a) is described. A partial Br 3 I exchange was observed when the demethylation of 6-methoxy precursor compound 4b was performed with Me 3 SiCl/NaI. This reaction is circumvented by the nucleophilic displacement of the MeO group under strong alkaline conditions. The halogenated 7-deaza-2'-deoxyxanthosine derivatives 1b,c show a decreased S-conformer population of the sugar moiety compared to the nonhalogenated 1a. They are expected to form stronger triplexes when they replace 1a in the 1 ¥ dA ¥ dT base triplet.Introduction. ± The synthesis of 7-deaza-2'-deoxyxanthosine (1a) via the glycosylation of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine was already reported from our laboratory in 1985 [1]. Later the nucleoside was prepared by a deamination/ demethylation route from 4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine 2'-deoxyribonucleoside 2a [2]. Compound 1a was incorporated into oligonucleotides without base protection by solid-phase synthesis by using phosphonate chemistry [2]. Triplexes containing 7-deazaxanthine in place of thymine showed a high third-strand-binding affinity under neutral conditions [2]. Contrary to the extremely labile 2'-deoxyxanthosine (3), in which the glycosylic bond hydrolyzes spontaneously under physiological conditions [3 ± 5], the glycosylic bond of the 7-deazapurine nucleoside 1a is resistant to −depurination× [1] [2].

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“…5). In contrast, small molecule crystal structures showing how the N-C bonds in substituted uridines respond to electron withdrawal in the uracil show no departure from trigonal planar geometry at N1 (43). Therefore, UDG funnels macromolecular DNA substrate-binding energy into catalytic power by conformationally closing to enforce substrate distortions, which would be energetically difficult in small molecule systems that lack large interfaces and transitions between two distinct rigid conformational states.…”

Section: Structural Implications For Two Coupled Stereoelectronic Effmentioning

confidence: 96%

Uracil-DNA glycosylase–DNA substrate and product structures: Conformational strain promotes catalytic efficiency by coupled stereoelectronic effects

Parikh

Walcher

Jones

et al. 2000

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

257

356

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Enzymatic transformations of macromolecular substrates such as DNA repair enzyme͞DNA transformations are commonly interpreted primarily by active-site functional-group chemistry that ignores their extensive interfaces. Yet human uracil-DNA glycosylase (UDG), an archetypical enzyme that initiates DNA base-excision repair, efficiently excises the damaged base uracil resulting from cytosine deamination even when active-site functional groups are deleted by mutagenesis. The 1.8-Å resolution substrate analogue and 2.0-Å resolution cleaved product cocrystal structures of UDG bound to double-stranded DNA suggest enzyme-DNA substrate-binding energy from the macromolecular interface is funneled into catalytic power at the active site. The architecturally stabilized closing of UDG enforces distortions of the uracil and deoxyribose in the flipped-out nucleotide substrate that are relieved by glycosylic bond cleavage in the product complex. This experimentally defined substrate stereochemistry implies the enzyme alters the orientation of three orthogonal electron orbitals to favor electron transpositions for glycosylic bond cleavage. By revealing the coupling of this anomeric effect to a delocalization of the glycosylic bond electrons into the uracil aromatic system, this structurally implicated mechanism resolves apparent paradoxes concerning the transpositions of electrons among orthogonal orbitals and the retention of catalytic efficiency despite mutational removal of active-site functional groups. These UDG͞DNA structures and their implied dissociative excision chemistry suggest biology favors a chemistry for base-excision repair initiation that optimizes pathway coordination by product binding to avoid the release of cytotoxic and mutagenic intermediates. Similar excision chemistry may apply to other biological reaction pathways requiring the coordination of complex multistep chemical transformations.

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Influence of substituents at the 5 position on the structure of uridine

Cited by 43 publications

References 7 publications

Additive CHARMM force field for naturally occurring modified ribonucleotides

Additive CHARMM force field for naturally occurring modified ribonucleotides

7‐Halogenated 7‐Deaza‐2′‐deoxyxanthine 2′‐Deoxyribonucleosides

Uracil-DNA glycosylase–DNA substrate and product structures: Conformational strain promotes catalytic efficiency by coupled stereoelectronic effects

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