Stereoelectronic effects in the hydrolysis of methyl ethylene phosphate

Taira, Kazunari; Fanni, Tahsin; Gorenstein, David G.

doi:10.1021/ja00317a077

Cited by 28 publications

(16 citation statements)

References 7 publications

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“…61 62 and none of the lactone 61 is observed, consistent with the stereoelectronic effect requirement for two app lone pairs to the breaking bond. Because lactone 62 is predicted to be the thermodynamically favored product, the stereoelectronic effect results of Deslongchamps would appear to be especially compelling.…”

Section: B Stereoelectronic Effects In Esters and Amides And Related ...supporting

confidence: 72%

“…Our laboratory has argued that a most important function of the enzyme is to provide for these conformational changes in the tetrahedral intermediate complex. 13,62 Maximization of both the normal and counterbalancing (see section IIIC) stereoelectronic effects sug- gests, as discussed in the theory section IIIB and detailed in Figure 2, that in acyl addition/elimination reactions where both bond making in the addition step and bond breaking in the elimination step are partially rate limiting, rotation about the scissile bonds during the reaction is essential. 13 The best stereoelectronic (and counterbalancing stereoelectronic) lone-pair orientation on N and O for C-N bond making is going to be the wrong orientation for optimal stereoelectronic (and counterbalancing) stereoelectronic interactions for C-0 bond breaking.…”

Section: B Serine Proteasesmentioning

confidence: 94%

“…Thus, the C-N overlap population is 0.264e in the 21 conformation, whereas it is 0.229e in the 20 conformation. 62 The presence of an app lone pair to the scissile C-N bond in the 20 conformation weakens this bond (reduces the overlap population). As expected from the double-bond-no-bond resonance description of the stereoelectronic effect, the C-02 overlap population in 20 (0.540e) is larger than in 21 (0.490e).…”

Section: B Theoretical Calculations On Acyl Additlon/ellminatlon Reac...mentioning

confidence: 99%

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Stereoelectronic effects in biomolecules

Gorenstein¹

1987

Chem. Rev.

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182

120

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Section: B Stereoelectronic Effects In Esters and Amides And Related ...supporting

confidence: 72%

Section: B Serine Proteasesmentioning

confidence: 94%

Section: B Theoretical Calculations On Acyl Additlon/ellminatlon Reac...mentioning

confidence: 99%

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Stereoelectronic effects in biomolecules

Gorenstein¹

1987

Chem. Rev.

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182

120

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“…This might well furnish additional insights into the enzyme process, and the preferred mechanism might also be a good guide in the development of artificial ribonuclease enzymes. A number of other studies had been devoted to similar questions, although generally with phenyl esters rather than with the normal leaving group of RNA itself (2)(3)(4)(5)(6)(7)(8).…”

Section: Cleavage Of Rna By Imidazole and Other Buffersmentioning

confidence: 99%

Recognition and catalysis in nucleic acid chemistry.

Breslow

1993

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

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The enzyme ribonuclease A catalyzes the cleavage ofRNA, using the imidazole groups of histidine-12 and histidine-119 as its principal catalytic groups. Model studies show that RNA can be cleaved by imidazole buffer itself and that, as in the enzyme, a bell-shaped pH vs. rate profile is seen. This indicates that one imidazole functions as a base, while the other, as the imidazolium ion, functions as an acid. However, in contrast to the enzymatic case, the simple model uses the imidazoles in sequential, rather than simultaneous, bifunctional catalysis. Mechanistic studies on this reaction and on the reactions of simple dinucleotides catalyzed by imidazle and other buffers establish the details of the process. The results let us propose a mechanism for the enzymatic process' different from the standard one; they also stimulated us to design an improved mimic of the enzyme that uses a mechanism like that proposed for the enzyme. Critical to the mechanistic studies is observation of the rearrangement of normal 3',5 RNA nudeotides to the 2',5" isomers. This led us to investigate the properties of DNA isomers in which a 2',5" link also replaces the normal 3',5" one. The results indicate that poor base stacking in a double helix with such links makes them less suitable as genetic units.procedure, we were able to show (10) that indeed imidazole buffer catalyzed the cleavage of an RNA, poly(U). As with the enzyme, we saw a bell-shaped pH vs. rate profile for the catalyzed process, with a rate maximum when both imidazole and protonated imidazolium ion were present (Fig. 1). However, it was clear that the two catalysts were not operating simultaneously, in contrast to the likely situation in the enzyme. The reaction was first order in buffer concentration ([buffer]) as shown in Fig. 2 The enzyme ribonuclease A hydrolyzes ribonucleic acid (RNA) by a two-stage mechanism in which first there is ester interchange to form a cyclic phosphate, with cleavage of the chain. Then the 2',3'-cyclic phosphate ester is hydrolyzed by the enzyme. The principal catalytic groups for both the cyclization and the hydrolysis are the imidazole rings of His-12 and His-119, although Lys41 also plays a role. In the classical mechanism seen in most textbooks, the cyclization is catalyzed as the basic imidazole of His-12 deprotonates the 2'-hydroxyl group, while the acidic imidazolium group of protonated His-119 acts to protonate the leaving oxygen atom of the departing nucleoside.Some years ago we initiated a project to investigate the cleavage of RNA by imidazole buffer itself (for a recent review, see ref. 1). If it did catalyze the process, we wanted to learn the detailed mechanism involved. This might well furnish additional insights into the enzyme process, and the preferred mechanism might also be a good guide in the development of artificial ribonuclease enzymes. A number of other studies had been devoted to similar questions, although generally with phenyl esters rather than with the normal leaving group of RNA itself (2-8).We first d...

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“…The inuence of oxygen electron lone pairs on P-O bonds has been demonstrated in a number of studies. For instance, in early Gorenstein and coworkers' papers [18][19][20] on phosphate and phosphorane compounds the ester P-O bonds were shown to change depending on the orientation of the lone pairs of the ester O atoms.…”

Section: Introductionmentioning

confidence: 99%