Phosphodiester bond cleavage

In contrast, the hairpin ribozyme (HPR) [107, 108], which catalyzes the reversible, site-specific phosphodiester bond cleavage of an RNA substrate, is unique in that the chemical steps of the reaction do not require involvement of a divalent metal ion [107-111]. This lack of an explicit metal ion requirement [112] makes the hairpin ribozyme an ideal target for theoretical studies aimed to characterize the contribution of generalized solvation provided by the solvated ribozyme on catalysis. 

Most RNAs are not made in their final functional forms as they peel off the DNA template (fig. 28.14). They must undergo backbone phosphodiester bond cleavages into smaller molecules (processing) and individual base changes... 

Figure 19-14. Proposed pathways for phosphodiester bond cleavage of DNA via LEE impact...

A recent study suggests that Pol IV and Pol V may also be involved in BER because of their intrinsic lyase activity (76). Shen et al. demonstrate relatively weak 5 -phosphodiester bond cleavage of an abasic site (AP/5 -dRP activity) by Pol IV and Pol V. Interestingly, several DNA polymerases from the X, A, and Y families exhibit lyase activity. Human Pol P, for example, exhibits strong AP/5 -dRP activity and is thought to be involved in the excision and incorporation of nucleotides during BER (77, 78). Furthermore, eukaryotic pol i, which is a Y-family homolog of Pol IV and Pol V, has also been shown to exhibit AP/5 -dRP activity (79). Additional studies are required to determine whether Pol IV and Pol V are involved in BER. 

Cassano AG, Anderson VE, Harris ME. Understanding the transi- 41. tion states of phosphodiester bond cleavage insights from heavy... 

Other authors found that a highly flexible crown ether - scaffold (103) constitutes a simplified activity - controllable catalytic system for phosphodiester bond cleavage of the same RNA model substrate (102). ... 

RNase will also catalyze phosphodiester bond cleavage in low molecular weight substrates, such as cyclic cytidine monophosphate (cCMP) to produce 5 -CMP (Eq. 4.21) ... 

Helicases and topoisomerase are distinct in that topoisomerases alter the linking number of the dsDNA by phosphodiester bond cleavage and reunion, whereas helicases simply disrupt the hydrogen bonds that hold the two strands of DNA duplex together. This is accomplished in a reaction that is conpled with the hydrolysis of a NTP, therefore helicases are also nncleoside-5 -triphosphatases. Some hehcases unwind not only DNA duplexes but also DNA-RNA hybrids and RNA dnplexes (Matson and Kaiser-Roger, 1990). The nnwinding of dsDNA may proceed in a 5 —> 3 direction (e.g. DnaB, E. coli helicases I and 111, and monse ATPase B) or a 3 —> 5 direction (e.g. E. coli helicases 11 and IV). 

Yamada, K., Takahashi, Y., Yamamura, H., Araki, S., Saito, K., Kawai, M. Phosphodiester bond cleavage mediated by a cycUc P-sheet peptide-based dinuclear zinc(II) complex. Chem. Commun. 2(N)0, 1315-1316. 

The discovery of nbozymes (Section 28 11) in the late 1970s and early 1980s by Sidney Altman of Yale University and Thomas Cech of the University of Colorado placed the RNA World idea on a more solid footing Altman and Cech independently discovered that RNA can catalyze the formation and cleavage of phosphodiester bonds—exactly the kinds of bonds that unite individual ribonucleotides in RNA That plus the recent discovery that ribosomal RNA cat alyzes the addition of ammo acids to the growing peptide chain in protein biosynthesis takes care of the most serious deficiencies in the RNA World model by providing precedents for the catalysis of biologi cal processes by RNA... 

DNA is not susceptible to alkaline hydrolysis. On the other hand, RNA is alkali labile and is readily hydrolyzed by dilute sodium hydroxide. Cleavage is random in RNA, and the ultimate products are a mixture of nucleoside 2 - and 3 -monophosphates. These products provide a clue to the reaction mechanism (Figure 11.29). Abstraction of the 2 -OH hydrogen by hydroxyl anion leaves a 2 -0 that carries out a nucleophilic attack on the phosphorus atom of the phosphate moiety, resulting in cleavage of the 5 -phosphodiester bond and formation of a cyclic 2, 3 -phosphate. This cyclic 2, 3 -phosphodiester is unstable and decomposes randomly to either a 2 - or 3 -phosphate ester. DNA has no 2 -OH therefore DNA is alkali stable. 

Heterocycles as agents for the cleavage of phosphodiester bonds in RNA 98CRV961. 

Schulz, W. G. Nieman, R. A. Skibo, E. B. Evidence for DNA phosphate backbone alkylation and cleavage by pyrrolo[l,2-a] benzimidazoles, small molecules capable of causing sequence specific phosphodiester bond hydrolysis. Proc. Natl. Acad. Sci. USA 1995, 92, 11854-11858. 

Considering that the phosphodiester bond is one of the most stable chemical linkages in nature, its cleavage is an obvious and challenging target for antibody catalysis. In an attempt to model a metal-independent mechanism, a... 

Figure 1. Phosphoiylation, dephosphorylation and cleavage of Ptdlns. PI3-K phosphorylates the inositol ring at D3, while PTEN dephosphotylates it at the same position. SHIP dephosphotylates 5-phosphotylated Ptdlns, PLOy hydrolyses the phosphodiester bond between the glycerol backbone and the inositol headgroup of Ptdlns (3,4)/ 2> releasing IP3.

Abstract The last few years have seen a considerable increase in our understanding of catalysis by naturally occurring RNA molecules, called ribozymes. The biological functions of RNA molecules depend upon their adoption of appropriate three-dimensional structures. The structure of RNA has a very important electrostatic component, which results from the presence of charged phosphodiester bonds. Metal ions are usually required to stabilize the folded structures and/or catalysis. Some ribozymes utilize metal ions as catalysts while others use the metal ions to maintain appropriate three-dimensional structures. In the latter case, the correct folding of the RNA structures can perturb the pKa values of the nucleo-tide(s) within a catalytic pocket such that they act as general acid/base catalysts. The various types of ribozyme exploit different cleavage mechanisms, which depend upon the architecture of the individual ribozyme. 

Fig. 3 Possible catalytic functions of metal ions in the cleavage of a phosphodiester bond. Metal ions can act as (a) a general acid catalyst, (b) a general base catalyst, (c) a Lewis acid that stabilizes the leaving group, (d) a Lewis acid that enhances the deprotonation of the attacking nucleophile, and (e) an electrophilic catalyst that increases the electrophilicity of the phosphorus atom...

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