The Reactivity of Nucleophilic Reagents toward the p-Nitrophenyl Phosphate Dianion<sup>1</sup>

Kirby, Anthony J.; Jencks, William P.

doi:10.1021/ja01092a036

Cited by 223 publications

(259 citation statements)

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(2 reference statements)

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“…This would be in line with the postulated resistance of phosphate monoester dianions to hydroxide attack 7 . The authors then find that the hydrolysis proceeds via an expansive transition state, with P-O distances of 2.65 and 2.75Å to the incoming nucleophile and departing leaving group respectively.…”

Section: Iii1 Free Energy Surface For P-nitrophenyl Phosphate Hydrolsupporting

confidence: 62%

“…Such pathways can in turn also be associative or dissociative in nature, depending on whether the reaction is dominated by bond-cleavage to the leaving group or bond-formation to the nucleophile as the system moves from the ground state to the transition 64 , kinetic isotope effects 2,65 , and examining entropies of activation 7 . However, the extent to which such tools can (even in combination) provide clear mechanistic insight has been questioned 14 , and in fact computational studies show that the interpretation of such mechanistic markers is far from clear, in part due to the fact that in many cases, phosphoryl transfer reactions can potentially occur through multiple equally viable mechanisms, even in solution 24,57 , and, additionally, in the case of concerted pathways, LFER can mask gradual changes in the nature of the transition state [16][17][18] .…”

Section: Ii1 Mechanistic Considerationsmentioning

confidence: 99%

“…1 This is of interest, as it has traditionally been argued that the small entropy of activation for the hydrolysis of phosphate monoester dianions is supportive of a dissociative (expansive) transition state 7 , whereas, as can be seen from Figs. 2 and 3, pNPP hydrolysis would appear to proceed through a more compact transition state than pNPS hydrolysis despite having a significantly smaller activation entropy.…”

Section: Species a -T S Solv -T S Conf -T S Totcalc -T S Totexp Pnppmentioning

confidence: 99%

“…As a result, phosphate esters have been the subject of extensive experimental 3,6-13 and theoretical [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] studies (though the precise mechanisms of both the solution and enzyme catalyzed reactions remain controversial, see e.g. [6][7][8]12,14,15,25,26,29,[33][34][35] ). In contrast, while there has been some significant work on the hydrolysis of sulfate esters (see e.g.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Kamerlin

2011

J. Org. Chem.

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Both phosphoryl and sulfuryl transfer are ubiquitous in biology, being involved in a wide range of processes, ranging from cell division to apoptosis. Additionally, it is becoming increasingly clear that enzymes that can catalyze phosphoryl transfer can often cross-catalyze sulfuryl-transfer (and vice versa).However, while there have been extensive experimental and theoretical studies performed on phosphoryl transfer, the body of available research on sulfuryl transfer is comparatively much smaller.The present work presents a direct theoretical comparison of p-nitrophenyl phosphate and sulfate monoester hydrolysis, both of which are considered prototype systems for probing phosphoryl and sulfuryl transfer respectively. Specifically, free energy surfaces have been generated using density functional theory, by initial geometry optimization in PCM using the 6-31+G* basis set and the B3LYP density functional, followed by single point calculations using the larger 6-311+G** basis set and the COSMO continuum model. The resulting surfaces have been then used to identify the relevant transition states, either by further unconstrained geometry optimization, or from the surface itself where possible.Additionally, configurational entropies were evaluated using a combination of the quasiharmonic approximation and the restraint release approach and added to the calculated activation barriers as a correction. Finally, the overall activation entropy was estimated by approximating the solvent contribution to the total activation entropy using the Langevin dipoles solvation model. We have reproduced both the experimentally observed activation barriers and the observed trend in the activation entropies with reasonable accuracy, as well providing a comparison of calculated and observed 15 N and 18 O kinetic isotope effects. We demonstrate that, counterintuitively, the hydrolysis of the p-nitrophenyl sulfate proceeds through a more expa show that the solvation effects upon moving from the ground state to the transition state are quite different for both reactions, suggesting that the enzymes that catalyze these reactions would need active 4 sites with quite different electrostatic preorganization for the efficient catalysis of either reaction (despite which many enzymes can catalyze both phosphoryl and sulfuryl transfer). We believe that such a comparative study is an important foundation for understanding the molecular basis for phosphatesulfate cross promiscuity within members of the alkaline phosphatase superfamily.

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Section: Iii1 Free Energy Surface For P-nitrophenyl Phosphate Hydrolsupporting

confidence: 62%

Section: Ii1 Mechanistic Considerationsmentioning

confidence: 99%

Section: Species a -T S Solv -T S Conf -T S Totcalc -T S Totexp Pnppmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Kamerlin

2011

J. Org. Chem.

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“…The same is true when the analysis ignores the fact that the water proton ultimately ends up on the phosphate (see more problems with this issue in the discussion in Section 4.1). This problem is further compounded by a tendency to take isotope (Hengge, 2002) and entropic (Kirby & Jencks, 1965a) effects, which are qualitatively difficult to interpret, and to use them as unique mechanistic markers supporting a dissociative mechanism, as was done in e.g. (Hoff & Hengge, 1998b ;Lassila et al 2011).…”

Section: What Is the Actual Mechanism Of Phosphate Hydrolysis And Relmentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

339

448

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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Mimicking Metallophosphatases: Revealing a Role for an OH Group with No Libido

Forconi

Williams

2002

Angew. Chem.

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Typically, descriptions of enzyme catalysis use multiple simultaneous interactions between the substrate and the active site to explain the remarkable efficiency which is normally observed. [1] This poses the intriguing question-do the different interactions operate cooperatively? That is, can a catalytic interaction have a bigger impact when it acts in concert with other complementary interactions than when it is used alone. This is difficult to mimic with simple compounds; usually when multiple interactions are introduced into a model system, it is found that they act independently rather than simultaneously, and such models generally do not rival enzyme efficiency. [2] Here we report how catalysis of phosphate monoester hydrolysis by an intramolecular OH group becomes much more effective when combined with catalysis by a dinuclear metal ion complex.We have incorporated phosphate monoesters 1 a ± c into dinuclear Co III complexes 2 a ± c. We have previously studied this type of complex as a structural and functional model for dinuclear metallophosphatases. [3] We wanted to investigate the effect of combining intramolecular general acid catalysis with this highly reactive core, as X-ray crystallography has revealed that as well as the metal ions in the active sites of metallophosphatase such as protein phosphatase-1 (PP-1) and kidney bean purple acid phosphatase (KBPAP), potentialIn summary, we have developed a new family of 1,4diphosphanes 1 with an imidazolidin-2-one backbone as chiral ligands and showed their utility in the hydrogenation of aenamides. The modular construction of this ligand class allows for wide structural diversity. Studies of this kind and mechanistic investigations are underway. Experimental SectionFor details on the synthesis of 1 a ± 1 k and their precursors, see Supporting Information.General procedure for the asymmetric hydrogenation of enamide 4: 1 (0.0074 mmol) was added to a solution of [Rh(cod) 2 ]BF 4 (2.5 mg, 0.0062 mmol; cod 1,5-cyclooctadiene) in CH 2 Cl 2 (2 mL). After the reaction mixture had been stirred at 20 8C for 20 min, enamide 4 (0.62 mmol) was added. The hydrogenation was performed at 20 8C under 1 atm of hydrogen for 12 h. The reaction mixture was passed through a short silica gel column to remove the catalyst. The enantiomeric excess and the reaction conversion were measured by chiral GC or HPLC without any further purification. The enantioselectivity was slightly decreased at a lower reaction temperature (95.7 % ee at 6 8C) or higher hydrogen pressure (95.2 % ee at 40 psi) with ligand 1 g. Other solvents such as acetone (95.6 % ee), THF (93.9 % ee), and MeOH (94.2 % ee) were also examined with 1 g as chiral ligand.[13] M.

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The Reactivity of Nucleophilic Reagents toward the p-Nitrophenyl Phosphate Dianion¹

Cited by 223 publications

References 2 publications

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Why nature really chose phosphate

Mimicking Metallophosphatases: Revealing a Role for an OH Group with No Libido

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The Reactivity of Nucleophilic Reagents toward the p-Nitrophenyl Phosphate Dianion1

Cited by 223 publications

References 2 publications

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Why nature really chose phosphate

Mimicking Metallophosphatases: Revealing a Role for an OH Group with No Libido

Contact Info

Product

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The Reactivity of Nucleophilic Reagents toward the p-Nitrophenyl Phosphate Dianion¹