Phosphodiester models for cleavage of nucleic acids

Abstract

Nucleic acids that store and transfer biological information are polymeric diesters of phosphoric acid. Cleavage of the phosphodiester linkages by protein enzymes, nucleases, is one of the underlying biological processes. The remarkable catalytic efficiency of nucleases, together with the ability of ribonucleic acids to serve sometimes as nucleases, has made the cleavage of phosphodiesters a subject of intensive mechanistic studies. In addition to studies of nucleases by pH-rate dependency, X-ray crystallography, amino acid/nucleotide substitution and computational approaches, experimental and theoretical studies with small molecular model compounds still play a role. With small molecules, the importance of various elementary processes, such as proton transfer and metal ion binding, for stabilization of transition states may be elucidated and systematic variation of the basicity of the entering or departing nucleophile enables determination of the position of the transition state on the reaction coordinate. Such data is important on analyzing enzyme mechanisms based on synergistic participation of several catalytic entities. Many nucleases are metalloenzymes and small molecular models offer an excellent tool to construct models for their catalytic centers. The present review tends to be an up to date summary of what has been achieved by mechanistic studies with small molecular phosphodiesters.

Mercury(II)-Catalyzed Cleavage, Isomerization and Depurination of RNA and DNA Model Compounds and Desulfurization of Their Phosphoromonothioate Analogs

“…The rate constants for the Hg(II)-independent reactions were consistent with those reported previously for similar model compounds under the same conditions [21]. The observation that cleavage is catalyzed more efficiently than isomerization (k Hg = 7.0 and 1.3 × 10 −6 M −n s −1 , respectively) is also in line with previous reports on catalysis by other metal ions [11], and suggests that Hg(II) exerts its catalytic effect mainly by assisting in the departure of the 5 -linked nucleoside. This assistance could take the form of either direct coordination of Hg(II) to the departing oxygen or proton transfer from an aqua ligand.…”

“…Metal ion-catalyzed cleavage of both RNA and DNA phosphodiester linkages has been investigated extensively to understand the mechanism of action of natural nucleases (including ribozymes) [1][2][3][4][5], as well as to develop artificial ones [6][7][8][9][10]. Comparative studies with phosphodiester and phosphorothioate model compounds have been instrumental in revealing coordination of catalytically important metal ions to the scissile linkage [11][12][13][14][15][16]. The catalytic activities of various metal ions reflect their binding affinities to oxygen and sulfur, with hard metal ions being more efficient in the cleavage of phosphates and soft ones in the cleavage of phosphorothioates.…”

Strict conformational demands of RNA cleavage in bulge-loops created by peptidyl-oligonucleotide conjugates

“…( 14 , 52 , 53 ) Such a phosphodiester transesterification reaction can be facilitated by various functional groups introduced into the conjugate structure, which can: (i) enhance the rate of deprotonation at the 2′-hydroxyl group, (ii) stabilize the phosphorane intermediate and (iii) the leaving group and/or (iv) promote the ‘in-line’ geometry, when the 2′-oxyanion enters (or the 5′-linked nucleotide leaves) the phosphorane intermediate. ( 53 , 54 ) In such an ‘in-line’ configuration, which is crucial for catalysis, the penta-coordinate intermediates assume trigonal bipyramidal geometry, with the 2′ and 5′ oxygens occupying apical positions around 180° from one to another ( 52 ). Arginine guanidinium groups of the catalytic peptide (acetyl-[LR] 4 G-CO 2 H or acetyl-[LRLRG] 2 -CO 2 H) are key in promoting catalysis ( 15 , 16 ).…”

“…Arginine guanidinium groups of the catalytic peptide (acetyl-[LR] 4 G-CO 2 H or acetyl-[LRLRG] 2 -CO 2 H) are key in promoting catalysis ( 15 , 16 ). They appear to act as proton shuttles ( 53 ) through various tautomeric forms, by facilitating the proton transfer between the attacking 2′-OH, non-bridging phosphate oxygen and departing 5′-O group. A few reports ( 55–57 ) provide evidence of synchronized action of two guanidinium groups in catalysis, when they are present in the same molecular structure.…”

Conformational Mobility and Efficiency in Supramolecular Catalysis. A Computational Approach to Evaluate the Performances of Enzyme Mimics

“…A relevant number of supramolecular catalysts were designed and synthesized to cleave phosphodiester bonds, due to their frequent presence in nature and to their reluctance to spontaneous hydrolysis. [15,16] Such artificial phosphodiesterases are typically based on the cooperation of metal cations acting as nucleophile carriers, Lewis acid activators, binding sites as well as promoters of the departure of leaving groups. [17][18][19][20][21][22][23][24][25] In spite of the widespread use of metals in these systems, a number of artificial (ribo)nucleases employ guanidinium groups as active functions on their own, [26][27][28][29] or in a synergic action with other active units.…”