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1.
Lönnberg H 《Organic & biomolecular chemistry》2011,9(6):1687-1703
RNA molecules participate in many fundamental cellular processes either as a carrier of genetic information or as a catalyst, and hence, RNA has received increasing interest both as a chemotherapeutic agent and as a target of chemotherapy. In addition the dual nature of RNA has led to the RNA-world concept, i.e. an assumption that the evolution at an early stage of life was based on RNA-like oligomers that were responsible for the storage and transfer of information and as catalysts maintained primitive metabolism. Accordingly, the kinetics and mechanisms of the cleavage of RNA phosphodiester bonds have received interest and it is hoped they will shed light on the mechanisms of enzyme action and on the development of artificial enzymes. The major mechanistic findings concerning the cleavage by small molecules and ions and their significance for the development of efficient and biologically applicable artificial catalysts for RNA hydrolysis are surveyed in the present perspective. 相似文献
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Barman J Acharya S Zhou C Chatterjee S Engström A Chattopadhyaya J 《Organic & biomolecular chemistry》2006,4(5):928-941
We here show that the electronic properties and the chemical reactivities of the internucleotidic phosphates in the heptameric ssRNAs are dissimilar in a sequence-specific manner because of their non-identical microenvironments, in contrast with the corresponding isosequential ssDNAs. This has been evidenced by monitoring the delta H8(G) shifts upon pH-dependent ionization (pK(a1)) of the central 9-guaninyl (G) to the 9-guanylate ion (G-), and its electrostatic effect on each of the internucleotidic phosphate anions, as measured from the resultant delta 31P shifts (pKa2) in the isosequential heptameric ssRNAs vis-à-vis ssDNAs: [d/r(5'-Cp1Ap2Q1p3Gp4Q2p5Ap6C-3'): Q1 = Q2 = A (5a/5b) or C (8a/8b), Q(1) = A, Q(2) = C (6a/6b), Q1 = C, Q2 = A (7a/7b)]. These oligos with single ionizable G in the centre are chosen because of the fact that the pseudoaromatic character of G can be easily modulated in a pH-dependent manner by its transformation to G- (the 2'-OH to 2-O- ionization effect is not detectable below pH 11.6 as evident from the N(1-Me)-G analog), thereby modulating/titrating the nature of the electrostatic interactions of G to G- with the phosphates, which therefore constitute simple models to interrogate how the variable pseudoaromatic characters of nucleobases under different sequence context (J. Am. Chem. Soc., 2004, 126, 8674-8681) can actually influence the reactivity of the internucleotide phosphates as a result of modulation of sequence context-specific electrostatic interactions. In order to better understand the impact of the electrostatic effect of the G to G- on the tunability of the electronic character of internucleotidic phosphates in the heptameric ssRNAs 5b, 6b, 7b and 8b, we have also performed their alkaline hydrolysis at pH 12.5 at 20 degrees C, and have identified the preferences of the cleavage sites at various phosphates, which are p2, p3 and p4 (Fig.3). The results of these alkaline hydrolysis studies have been compared with the hydrolysis of analogous N(1-Me)-G heptameric ssRNA sequences 5c, 7c and 8c under identical conditions in order to establish the role of the electrostatic effect of the 9-guanylate ion (and the 2'-OH to 2-O- ionization) on the internucleotidic phosphate. It turned out that the relative alkaline hydrolysis rate at those particular phosphates (p2, p3 and p4) in the N(1-Me)-G heptamers was reduced from 16-78% compared to those in the native counterparts [Fig. 4, and ESI 2 (Fig. S11)]. Thus, these physico-chemical studies have shown that those p2, p3 and p4 phosphates in the native heptameric RNAs, which show pKa2 as well as more deshielding (owing to weaker 31P screening) in the alkaline pH compared to those at the neutral pH, are more prone to the alkaline hydrolysis because of their relatively enhanced electrophilic character resulting from weaker 31P screening. This screening effect originates as a result of the systematic charge repulsion effect between the electron cloud in the outermost orbitals of phosphorus and the central guanylate ion, leading to delocalization of the phosphorus p(pi) charge into its dpi orbitals. It is thus likely that, just as in the non-enzymatic hydrolysis, the enzymatic hydrolysis of a specific phosphate in RNA by general base-catalysis in RNA-cleaving proteins (RNase A, RNA phosphodiesterase or nuclease) can potentially be electrostatically influenced by tuning the transient charge on the nucleobase in the steric proximity or as a result of specific sequence context owing to nearest-neighbor interactions. 相似文献
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Flp provides a unique opportunity to apply the tools of chemical biology to phosphoryl transfer reactions. Flp and other tyrosine recombinases catalyze site-specific DNA rearrangements via a phosphotyrosine intermediate. Unlike most related enzymes, Flp's nucleophilic tyrosine derives from a different protomer than the remainder of its active site. Because the tyrosine can be supplied exogenously, nonnatural synthetic analogs can be used. Here we examine the catalytic role of Flp's conserved H305. DNA cleavage was studied using a peptide containing either tyrosine (pKa congruent with 10) or 3-fluoro-tyrosine (pKa congruent with 8.4). Religation was studied using DNA substrates with 3'-phospho-cresol (pKa congruent with 10) or 3'-para-nitro-phenol (pKa congruent with 7.1). In both cases, the tyrosine analog with the lower pKa specifically restored the activity of an H305 mutant. These results provide experimental evidence that this conserved histidine functions as a general acid/base catalyst in tyrosine recombinases. 相似文献
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Kirby AJ Lima MF da Silva D Roussev CD Nome F 《Journal of the American Chemical Society》2006,128(51):16944-16952
The hydrolysis of methyl 8-dimethylamino-1-naphthyl phosphate 4 and its reactions with a representative range of nucleophiles are catalyzed by the dimethylammonium group at acidic pH with rate accelerations of the order of 106. The reaction persists up to pH 7 because the strong intramolecular hydrogen bond, which is the key to efficient general acid catalysis, is present also in the reactant. The sensitivity to the basicity of the nucleophile (Br?nsted beta(nuc) = 0.29) lies between values measured previously for mono- and triesters. The comparisons suggest that general acid catalyzed reactions of phosphate mono- or diesters with strongly basic oxyanion nucleophiles (like those derived from a serine oxygen or a bound water molecule in an enzyme active site) will be fastest when their negative charges are neutralized by protonation. Reactions with NH2OH and its N-methylated derivatives show an apparent alpha-effect, but NH2OMe reacts no faster than a primary amine of similar basicity. It is suggested that the reaction involving NH2OH as an oxygen nucleophile proceeds through the pre-equilibrium formation of the tautomer H3N+-O- as the active nucleophile: ab initio calculations support this idea. 相似文献
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Gao H Ke Z DeYonker NJ Wang J Xu H Mao ZW Phillips DL Zhao C 《Journal of the American Chemical Society》2011,133(9):2904-2915
Density functional theory (DFT) calculations were used to study the mechanism for the cleavage reaction of the RNA analogue HpPNP (HpPNP = 2-hydroxypropyl-4-nitrophenyl phosphate) catalyzed by the dinuclear Zn(II) complex of 1,3-bis(1,4,7-triazacyclonon-1-yl)-2-hydroxypropane (Zn(2)(L(2)O)). We present a binding mode in which each terminal phosphoryl oxygen atom binds to one zinc center, respectively, and the nucleophilic 2-hydroxypropyl group coordinates to one of the zinc ions, while the hydroxide from deprotonation of a water molecule coordinates to the other zinc ion. Our calculations found a concerted mechanism for the HpPNP cleavage with a 16.5 kcal/mol reaction barrier. An alternative proposed stepwise mechanism through a pentavalent oxyphosphorane dianion reaction intermediate for the HpPNP cleavage was found to be less feasible with a significantly higher energy barrier. In this stepwise mechanism, the deprotonation of the nucleophilic 2-hydroxypropyl group is accompanied with nucleophilic attack in the rate-determining step. Calculations of the nucleophile (18)O kinetic isotope effect (KIE) and leaving (18)O KIE for the concerted mechanism are in reasonably good agreement with the experimental values. Our results indicate a specific-base catalysis mechanism takes place in which the deprotonation of the nucleophilic 2-hydroxypropyl group occurs in a pre-equilibrium step followed by a nucleophilic attack on the phosphorus center. Detailed comparison of the geometric and electronic structure for the HpPNP cleavage reaction mechanisms in the presence/absence of catalyst revealed that the catalyst significantly altered the determining-step transition state to become far more associative or tight, that is, bond formation to the nucleophile was remarkably more advanced than leaving group bond fission in the catalyzed mechanism. Our results are consistent with and provide a reliable interpretation for the experimental observations that suggest the reaction occurs by a concerted mechanism (see Humphry, T.; Iyer, S.; Iranzo, O.; Morrow, J. R.; Richard, J. P.; Paneth, P.; Hengge, A. C. J. Am. Chem. Soc. 2008, 130, 17858-17866) and has a specific-base catalysis character (see Yang, M.-Y.; Iranzo, O.; Richard, J. P.; Morrow, J. R. J. Am. Chem. Soc. 2005, 127, 1064-1065). 相似文献
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Knight DA Delehanty JB Goldman ER Bongard J Streich F Edwards LW Chang EL 《Dalton transactions (Cambridge, England : 2003)》2004,(13):2006-2011
4-(1,4,7,10-Tetraazacyclotetradec-1-yl)methylbenzoic acid (cycmba, 1) has been synthesized, as a step towards the eventual development of sequence-specific hydrolytic complexes. A cobalt(III) complex of 1, [Co(cycmba)Cl2]Cl.1.5H2O (.1.5H2O) was found to be active against both an activated phosphodiester compound, bis(nitrophenyl)phosphate (BNPP), and supercoiled DNA. The presence of the benzoate group depresses the rate of hydrolysis of the ligand-Co(III) system at neutral pH, as confirmed by the kinetics results of a methyl ester analog. The ability of (2.1.5H2O) to bind to solid substrates and remain active was also demonstrated by attachment of the molecule to agarose beads. 相似文献
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Plots of log k(0) vs pH for the cyclization of trifluoroethyl and phenyl 2-aminomethylbenzoate to phthalimidine at 30 degrees C in H(2)O are linear with slopes of 1.0 at pH >3. The values of the second-order rate constants k(OH) for apparent OH(-) catalysis in the cyclization reactions are 1.7 x 10(5) and 5.7 x 10(7) M(-)(1) s(-)(1), respectively. These rate constants are 10(5)- and 10(7)-fold greater than for alkaline hydrolysis of trifluoroethyl and phenyl benzoate. The k(OH) for cyclization of the methyl ester is 7.2 x 10(3) M(-)(1) s(-)(1). Bimolecular general base catalysis occurs in the intramolecular nucleophilic reactions of the neutral species. The value of the Bronsted coefficient beta for the trifluoroethyl ester is 0.7. The rate-limiting step in the general base catalyzed reaction involves proton transfer in concert with leaving group departure. The mechanism involving rate-determining proton transfer exemplified by the methyl ester in this series (beta = 1.0) can then be considered a limiting case of the concerted mechanism. General acid catalysis of the neutral species reaction or a kinetic equivalent also occurs when the leaving group is good (pK(a) = 12.4). That the mechanism and/or rate-determining step of the intramolecular aminolysis reactions is different than in bimolecular reactions or the intramolecular reactions of other esters is attributed to the excellent steric fit of the nucleophile to the reaction center of the 2-aminomethylbenzoate esters. 相似文献
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Hyeong-Won Ryu Young Cho Dae-Young Kim Thong-Sung Ko 《Reaction Kinetics and Catalysis Letters》1999,66(1):127-132
Phosphodiester cleavage of BNPP can be accelerated by various degradative receptors including enzymes. In the hydrolytic cleavage
of BNPP, a bell-shaped receptor concentration-rate profile composed of a positive-catalysis phase at low receptor concentrations
and a negative-catalysis phase at excess receptor concentration was observed. The negative catalysis can be explained by nonproductive
binding, leading to an increase of the activation energy barrier and a decrease of the reaction rate. 相似文献
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Fristrup P Jensen T Hoppe J Norrby PO 《Chemistry (Weinheim an der Bergstrasse, Germany)》2006,12(20):5352-5360
An analysis of product distributions in the Tsuji-Trost reaction indicates that several instances of reported "memory effects" can be attributed to slow interconversion of the initially formed syn- and anti-[Pd(eta3-allyl)] complexes. Addition of chloride triggers a true memory effect, in which the allylic terminus originally bearing the leaving group has a higher reactivity. The latter effect, termed regioretention, can be rationalized by ionization from a palladium complex bearing a chloride ion, forming an unsymmetrically substituted [Pd(eta3-allyl)] complex. DFT calculations verify that the position trans to the phosphine ligand is more reactive both in the initial ionization and in the subsequent nucleophilic attack. 相似文献
15.
J. S. Yadav B. V. S. Reddy K. Sadashiv K. Harikishan A. V. Narsaiah 《Journal of molecular catalysis. A, Chemical》2004,220(2):153-157
Aziridines smoothly react with acid anhydrides in the presence of a catalytic amount of scandium triflate under mild reaction conditions to afford the corresponding β-aminoacetates, benzoates and propionates in high yields with high regioselectivity. 相似文献
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Rates of cleavage of Me3MR compounds (M = Si, R = m-ClC6H4CH2, p-NO2C6H4CH2, Ph2CH, 9-fluorenyl, and 2-benzothienyl; M = Sn, R = m-ClC6H4CH2, Ph2CH, 2-benzothienyl) have been measured in Me2SO/MeOH/MeONa, Me2SO/EtOH/EtONa, and Me2SO/H2O/HONMe4 media containing varying amounts of the hydroxylic component. The variations in the slopes of the log krel H plots are consistent with the view that a water or alcohol molecule provides electrophilic assistance in the rate-determining step for the tin compounds with R = m-ClC6H4CH2 and 2-benzothienyl, while for the silicon compounds, and possibly for the tin compound with R = Ph2CH, carbanions are liberated in the rate-determining step. 相似文献
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O-GlcNAcase catalyzes the removal of N-acetylglucosamine residues from serine and threonine residues of post-translationally modified proteins using a catalytic mechanism involving substrate-assisted catalysis and general acid/base catalysis. Since thioglycosides are widely perceived as resistant to hydrolysis by glycosidases, it was surprising to find that O-GlcNAcase also catalyzes the efficient hydrolysis of S-glycosides. Br?nsted analyses and pH-activity studies of the O-GlcNAcase-catalyzed hydrolysis of a series of aryl S- and O-glycosides reveal that O-GlcNAcase effects hydrolysis of thioglycosides without the assistance of general acid catalysis. alpha-Deuterium kinetic isotope effects for O- and S-glycosides, as well as Taft-like analyses using N-fluoroacetyl-beta-glycosides, suggest that O-GlcNAcase accomplishes hydrolysis of thioglycosides by stabilizing late transition states. For S-glycosides this transition state shows greater nucleophilic participation from the 2-acetamido group than for O-glycosides. The rate constants governing the O-GlcNAcase-catalyzed hydrolysis of O- and S-glycosides as compared to those previously determined for the spontaneous hydrolysis of structurally similar O,O- and O,S-acetals show a similar ratio. O-GlcNAcase therefore demonstrates similar catalytic proficiency toward both O- and S-glycosides. We conclude that O-GlcNAcase is a bifunctional catalyst capable of efficiently cleaving thioglycosides without general acid catalysis, an observation that may have biological implications. 相似文献
19.
《Journal of organometallic chemistry》1987,320(2):163-170
A new procedure has been developed for removing the SiCl3 group from α-trichlorosilyl-substituted amines. In this procedure the trichlorosilyl substrate is treated first with amine hydrochloride in CH3CN, followed by hydrolysis with aqueous hydroxide. Using this sequence, amines corresponding to replacement of the trichlorosilyl group with hydrogen can be conveniently isolated in good yields for all tested cases. Evidence suggests the intermediacy of an unstable chlorosilane species formed by probable nucleophilic attack of chloride. In conjunction with the addition reaction fo HSiCl3 to enamines to form the α-trichlorisilyl amines, the cleavage completes a new method for the transformation of enamines to amines which could be a useful alternative to either catalytic hydrogenation or metal hydride reduction. 相似文献
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We present 2-dimensional potential energy surfaces and optimised transition states (TS) for water attack on a series of substituted phosphate monoester monoanions at the DFT level of theory, comparing a standard 6-31++g(d,p) basis set with a larger triple-zeta (augmented cc-pVTZ) basis set. Small fluorinated model compounds are used to simulate increasing leaving group stability without adding further geometrical complexity to the system. We demonstrate that whilst changing the leaving group causes little qualitative change in the potential energy surfaces (with the exception of the system with the most electron withdrawing leaving group, CF(3)O(-), in which the associative pathway changes from a stepwise A(N) + D(N) pathway to a concerted A(N)D(N) pathway), there is a quantitative change in relative gas-phase and solution barriers for the two competing pathways. In line with previous studies, in the case of OCH(3), the barriers for the associative and dissociative pathways are similar in solution, and the two pathways are equally viable and indistinguishable in solution. However, significantly increasing the stability of the leaving group (decreasing proton affinity, PA) results in the progressive favouring of a stepwise dissociative, D(N) + A(N), mechanism over associative mechanisms. 相似文献