<b>Neighboring Group Participation in Phosphate Ester Hydrolysis</b>

Clark, V. M.; Kirby, Anthony J.

doi:10.1021/ja00905a043

Cited by 32 publications

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“…A demonstration of this statement comes from the hydrolysis of compound 2. In fact, when we carried out, at room temperature, the hydrolysis on pure compound 2, synthesized by using the procedure reported by Clark and Kirby, 17 we observed (by following the reaction course through 31 P NMR spectroscopy) the immediate appearance of a broad signal at δ 31P = −3.7 ppm, ascribed to TBP1 and TBP2, probably in equilibrium. After a few minutes, a sharp signal of TBP1 (δ 31P = −3.8 ppm) and a high-intensity signal of phosphoric acid (δ 31P = +0.7 ppm), together with a low-intensity signal of 4, appeared (see Scheme 1).…”

Section: Hydrolysis Of Cyclic Phosphatementioning

confidence: 88%

“…17 The structure of 2 (or of its cyclohexylammonium salt) was ascertained in non-hydrolytic conditions; its spectral data in different solvents are as follows: Compound 2 (0.010 g, 0.074 mmol) was dissolved in D 2 O (0.7 mL) in an NMR tube. In the 31 P NMR spectrum, immediately the presence of compounds TBP1 (δ = −3.8 ppm), D 3 PO 4 , and 4 in 20:10:1 relative height were observed.…”

Section: Behavior Of 2-hydroxy-5-methylene-132-dioxaphospholan-4-onmentioning

confidence: 99%

“…and Kirby,17 is involved as an intermediate. Consequently, they proposed the formation of a cyclic Scheme 1 Mechanism of non-enzymatic hydrolysis of PEP.…”

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confidence: 99%

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The Phosphoenolpyruvate Phosphorylation: A Self-Organized Mechanism with Implications to Understand the RNA Transformations

Baccolini

Boga

Micheletti

2010

Phosphorus, Sulfur, and Silicon and the Related Elements

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In this article, we present a study about the non-enzymatic hydrolysis of phosphoenolpyruvate (PEP) by following the reaction course through 31 P NMR spectroscopy. We have demonstrated that PEP in water exists mainly as a very stable cyclic pentacoordinate phosphorus compound in equilibrium with other cyclic forms. This explains the PEP stability in water. In contrast, after addition of an alcohol to a PEP aqueous solution, other very unstable cyclic pentacoordinated intermediates are formed, which immediately collapse, giving a feasible phosphorylation of the alcohol. It is known that cyclic pentacoordinated phosphorus intermediates are favored over the corresponding acyclic intermediates by a factor of 10 6 -10 8 , and this preference, found also in this study, might be the "driver mechanism" able to overcome the clutter of abiotic chemistry, thus permitting formation of pre-RNA molecules probably with a "self-organized process."

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Section: Hydrolysis Of Cyclic Phosphatementioning

confidence: 88%

Section: Behavior Of 2-hydroxy-5-methylene-132-dioxaphospholan-4-onmentioning

confidence: 99%

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The Phosphoenolpyruvate Phosphorylation: A Self-Organized Mechanism with Implications to Understand the RNA Transformations

Baccolini

Boga

Micheletti

2010

Phosphorus, Sulfur, and Silicon and the Related Elements

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“…[89] However, in the case of five-membered ring anhydrides, attack on the phosphate group (attack 2) can prevail. [90,91] Notably, phosphoalaninates of d4T phosphoramidates exhibited an anti-HIV effect comparable to the parent compound, d4T. [92] The final activation step of phosphoramidates is the cleavage of the PÀN bond of the phosphoalanine intermediate to generate the monophosphate nucleoside analogue.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

2009

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Prodrug technologies aimed at delivering nucleoside monophosphates into cells (protides) have proved to be effective in improving the therapeutic potential of antiviral and anticancer nucleosides. In these cases, the nucleoside monophosphates are delivered into the cell, where they may then be further converted (phosphorylated) to their active species. Herein, we describe one of these technologies developed in our laboratories, known as the phosphoramidate protide method. In this approach, the charges of the phosphate group are fully masked to provide efficient passive cell-membrane penetration. Upon entering the cell, the masking groups are enzymatically cleaved to release the phosphorylated biomolecule. The application of this technology to various therapeutic nucleosides has resulted in improved antiviral and anticancer activities, and in some cases it has transformed inactive nucleosides to active ones. Additionally, the phosphoramidate technology has also been applied to numerous antiviral nucleoside phosphonates, and has resulted in at least three phosphoramidate-based nucleotides progressing to clinical investigations. Furthermore, the phosphoramidate technology has been recently applied to sugars (mainly glucosamine) in order to improve their therapeutic potential. The development of the phosphoramidate technology, mechanism of action and the application of the technology to various monophosphorylated nucleosides and sugars will be reviewed.

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“…If the frcc acid of the dimethyl ester was dissolved in uater atid left for ti brief time without the addition of cyclohexylamine, however, the ester groups were hytlrolyzctl with remarkable r,ipidity (see Results). This indicates that ii hydrolysis mechanism involving acid catalysis as well ;IS iicighboriiig group participation (Clark and Kirby, 1963), pentacovalent phosphorus intcrmedintes and pseudorotational conversions (Benkovic a n d Shray, 1969) may be operating.…”

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confidence: 99%

Analogs of phosphoenolpyruvate. Specificity of pyruvate kinase from rabbit muscle

Kenyon¹,

Stubbe²

1971

Biochemistry

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Several compounds with structures analogous to phosphoenolpyruvate were synthesized for the purpose of investigating the specificity o f pyruvate kinase (EC 2.7.1.40). Contrary to the report of A. E. Woods et al. [Biochemistry 9, 2334[Biochemistry 9, (1970], it has been found that phosphoenol-a-ketobutyrate is a pseudosubstrate in the pyruvate kinase reaction. Phosphoenol-3-bromopyruvate was also shown to be a pseudosubstrate, but, within the limits of detection, phosphoenol-3-phenylpyruvate was inactive. The stereochemistries of the E and Z isomers of both phosphoenol-a-ketobutyrate and I n a recent paper Woods et al. (1970) reported the synthesis of several new homologs of phosphoenolpyruvate (PEP)' and presented evidence to show that none of these homologs, including phosphoenol-a-ketobutyrate, was active as a pseudosubstrate in the pyruvate kinase (EC 2.7.1.40) reaction. We have synthesized several analogs of PEP (l), includingWe wish to present evidence to show that phosphoenol-aketobutyrate (4) is a relatively slowly reacting pseudosubstrate for pyruvate kinase, that phosphoenol-3-bromopyruvate (7) is even more reactive, but that no detectable reaction was observed with phosphoenol-3-phenylpyruvate (9) or the other analogs listed. We have also made stereochemical assignments for the E and Z isomers of both phosphoenol-a-ketobutyrate and phosphoenol-3-bromopyruvate using nrnr spectroscopy and have shown that Z-phosphoenol-0-ketobutyrate gives 2-9.phosphoenol-3-bromopyruvate were assigned using nuclear magnetic resonance spectroscopy.(2)-Phosphoenol-a-ketobutyrate has been shown to yield (3R)-[3-2H]a-ketobutyrate stereospecifically when the enzymatic reaction was carried out in DzO.This corresponds to the addition of deuterium at C-3 on the 2 4 , 3-re face of the (Z)-phosphoenol-a-ketobutyrate or its mechanistic equivalent in the enzyme-catalyzed reaction. This result confirms recent similar findings of Bondinell and Sprinson [Biochem. Biophys. Res.

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Neighboring Group Participation in Phosphate Ester Hydrolysis

Cited by 32 publications

References 0 publications

The Phosphoenolpyruvate Phosphorylation: A Self-Organized Mechanism with Implications to Understand the RNA Transformations

The Phosphoenolpyruvate Phosphorylation: A Self-Organized Mechanism with Implications to Understand the RNA Transformations

Aryloxy Phosphoramidate Triesters: a Technology for Delivering Monophosphorylated Nucleosides and Sugars into Cells

Analogs of phosphoenolpyruvate. Specificity of pyruvate kinase from rabbit muscle

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