Metal ions phosphodiester hydrolysis

A series of diaquatetraaza cobalt(III) complexes accelerated the hydrolysis of adenylyl(3 -50adenosine (ApA) (304), an enhancement of 10 -fold being observed with the triethylenetetramine complex (303) at pH 7. The pentacoordinated intermediate (305), which is formed with the complex initially acting as an electrophilic catalyst, then suffers general acid catalysis by the coordination water on the Co(III) ion to yield the complexed 1,2-cyclic phosphate (306), the hydrolysis of which occurs via intracomplex nucleophilic attack by the metal-bound hydroxide ion on the phosphorus atom. Neomycin B (307) has also been shown to accelerate the phosphodiester hydrolysis of ApA (304) more effectively than a simple unstructured diamine. 

RNA hydrolysis, 45 285-287, 297-299 metalloenzymes, 45 251-252 bleomycin, 45 252-260, 299 nucleic acid hydrolysis metal ions and, 45 283-285 by oligonucleotide modified with metal complexes, 45 297-299 of phosphodiesters, 45 251, 287-297 by ribozymes, 45 285-287 cleavage by iron bleomycin, 43 140 polymerase, arsonomethyl phosphonate analogue, 44 201-202 substructures, 43 133-134 transfer... 

Wall et al. built a binuclear copper(II) complex 43 in order to see acceleration of phosphodiester cleavage (52). With the substrate (50 p.M) shown, the reaction might be considered as a model for the first step of the hydrolysis of RNA, in which the alcohol function of the side chain intramolecularly attacks the Cun-activated phosphate as a nucleophile for a ring closure reaction. Compared to an analogous mononuclear complex 44 (at 1 mM), a rate constant ca. 50 times larger for 43 (at 1 mM) was observed at 25°C and pH 7, implying that the two metal ions probably cooperate. An analogous zinc(II) complex 45 was reported only as a structural model for the active site of phospholi-... 

The 3 -5 proofreading exonuclease is called into action when an incorrect dNMP is added to the 3 terminus. The 3 -5 exonuclease is located in a separate domain with a distinct active site. The chemical reaction of the exonuclease proceeds by hydrolysis (see Fig. lb), but it is remarkably similar to the polymerase reaction. Specifically, two metal ions catalyze the reaction metal ion A activates water to form a hydroxyanion nucleophile that attacks the phosphodiester bond of the 3 terminal mismatched nucleotide. Metal B stabilizes the developing charge on the dNMP leaving group. 

The metal-dependent hydrolase class of enzymes uses catalytic metal ion(s) along with key active-site side chains to catalyze the hydrolysis of a wide variety of biologically important substrates, including carbohydrates, peptides, proteins, nucleotides, phosphodiesters, and xenobiotics. Interest in understanding the mechanisms of... 

The first step in RNA hydrolysis is the intramolecular nucleophilic attack of the phosphorus atom by the 2 -OH of ribose. This step is activated by the coordination of the phosphodiester linkage in RNA to the lanthanide(III) ion in the bimetallic cluster [R 2(OH)2] , since the electrons are withdrawn by the metal ion from the phosphorus atom. This electron withdrawal promotes the electrophilicity of the P atom, although it is not so drastic as the effect achieved by the Ce(IV) in DNA hydrolysis (cf. sect. 5). Furthermore, the hydroxide ion bound to another lanthanide(III) ion in the bimetallic cluster functions as a general base catalyst, and enhances the electrophilicity of the 2 -OH by removing its proton. Alternatively, the 2 -OH is directly coordinated to this metal ion, and its dissociation to alkoxide ion is facilitated. In this way, both the nucleophilic center (the oxygen in the 2 -OH) and the electrophilic center (the phosphorus atom) are simultaneously activated by the bimetallic cluster, and thus the intramolecular nucleophilic attack proceeds efficiently. 

DNase I is an endonuclease that catalyzes the hydrolysis of phosphodiester bonds by nucleophilic attack on 3 O-P. The enzyme activity requires divalent metal ion cofactors such as Mg " and Ca or Mn +. DNase I binds to the minor groove of dsDNA and cleaves each strand independently. The often observed sequence preference and different cleavage rates of DNase I are largely structural and are related to sequence-dependent variations of the double helix such as groove width, local rigidity to bending, radial asymmetry, and accessibility to backbone phosphates (26,29,33,34). 

Gomez-Tagle P, Vargas-Zuniga I, Taran O, Yatsimirsky AK. Solvent effects and alkali metal ion catAysis in phosphodiester hydrolysis. J Org Chem. 2006 71 9713-9722. de Souza EF, lonescu LG. MiceUar-catAyzed reactions of a phosphate ester effect of the dielectric constant of the medium. Colloid Surf A. 1999 149 609-615. Stockbridge RB, Wolfenden R. Phosphate monoester hydrolysis in cyclohexane. JAm Chem Soc. 2009 131 18248-18249. 

Lanthanide(III) and other elements in lanthanide series are very effective catalysts for the hydrolysis of the phosphodiester linkages in RNA, whereas nonlanthanide metal ions are virtually inactive." The pseudo-first-order rate constant for the hydrolysis of adenylyl-(3 5 )adenosine (ApA) by LuCls (5 mM) at pH 7.2 and 30°C is 0.19 min", which gives 10 -fold rate acceleration compared to rate of hydrolysis of ApA under the same reaction conditions but in the absence of LuClj. The product is an equimolar mixture of adenosine and... 

Ce(IV) ions efficiently catalyse the hydrolysis of phospho monoesters in nucleotides under physiological conditions. The proposed mechanism for the hydrolysis is illustrated in (217).189 Uranyl cations (U021) catalyse the hydrolysis of aggregated and non-aggregated p-nitrophenyl phosphodiesters such as (218)/(219) and (220), respectively.190 Bis(/>-nitrophenyl) phosphate (218) hydrolysis is accelerated ca 2.8 x 109-fold by Th(IV) cations in aqueous Brij micelles.191 The reactivity of Th(IV) towards (219) and (221 R = Et, C16H33) also exceeds that of uranyl ion190 and is comparable to that of Ce(IV) and exceeds that of other metal cations. 

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