Phosphate monoester, hydrolysis

The mechanism of phosphate ester hydrolysis by hydroxide is shown in Figure 1 for a phosphodiester substrate. A SN2 mechanism with a trigonal-bipyramidal transition state is generally accepted for the uncatalyzed cleavage of phosphodiesters and phosphotriesters by nucleophilic attack at phosphorus. In uncatalyzed phosphate monoester hydrolysis, a SN1 mechanism with formation of a (POj) intermediate competes with the SN2 mechanism. For alkyl phosphates, nucleophilic attack at the carbon atom is also relevant. In contrast, all enzymatic cleavage reactions of mono-, di-, and triesters seem to follow an SN2... 

Figure 4. Possible mechanisms of phosphate monoester hydrolysis by protein phosphatase 1.

Methyl-p-nitrophenyl phosphate coordinated to the two metal centers in 37 undergoes hydrolysis by a two-step addition-elimination mechanism [73]. The free phosphate hydrolyzes by a concerted mechanism. In both phosphate monoester and diester hydrolysis, the two Co(m) centers in 32 and 37 stabilize the five-coordinate phosphate species (transition state or intermediate) by bringing the phosphate and nucleophile together. This stabilization leads to a change in mechanism from dissociative to concerted for a phosphate monoester hydrolysis [96] and from concerted to stepwise for phosphate diester hydrolysis [73]. 

Aqvist J, Kolmodin K, Florian J, Warshel A. Mechanistic alternatives in phosphate monoester hydrolysis what conclusions can be drawn from available experimental data Chem. Biol. 

In the case of phosphate monoester hydrolysis by PTPases it has been argued that reported 0 isotope effects for the non-bridge phosphate oxygens, ( max/KTti) o -6ridge> show that the reacting groups are unprotonated [44]. However, the 1 )non-bridge values were then corrected, by the isotope effect... 

Calculations of heavy atom kinetic isotope effect in phosphate monoester hydrolysis... 

Phosphate monoester hydrolysis 133 Phosphate diester and triester hydrolysis 137 References 173... 

Scheme 32 Phosphate monoester hydrolysis catalyzed by alkaline phosphatase.

As with amide hydrolysis reactions, extensive mechanistic studies of metal-mediated phosphate monoester hydrolysis reactions have been performed using exchange inert mononuclear Co(III) complexes.9,188-202 To date, only a few zinc complexes that promote phosphate monoester hydrolysis have been reported. A binuclear zinc complex supported by a macrocyclic cryptate ligand (Fig. 36)... 

Fig. 36 Phosphate monoester hydrolysis promoted by a bizinc cryptand complex.

Similar to studies of phosphate monoester hydrolysis reactions, extensive kinetic and mechanistic investigations involving exchange inert Co(III) compounds have yielded insight into the pathways of these reactions.9,192,194,197,198,200,211-220... 

Although phosphate monoesters chiral by virtue of oxygen isotope substitutions cannot be used in stereochemical studies of phosphate monoester hydrolysis (since there are only three stable isotopes of oxygen), they have been used profitably in studies of phosphoryl transfer reactions relevant to the question of the intermediacy of monomeric metaphosphate anion in phosphoryl transfer reactions (see Section III,A). The laboratories of Knowles and Lowe have reported general methods for the synthesis of phosphate monoesters chiral by virtue of oxygen isotope substitution, and these syntheses are summarized in this section. 

Jencks, Skoog, and Herschlag have carried out hallmark studies of the nature of the transition state in the phosphoryl group transfer reaction, including phosphate monoester hydrolysis. 

Alkaline phosphatase (EC 3.1.3.1. Table 1, entry 8) also possesses a wide range of promiscuous activities. Some of them differ from the native phosphate monoesters hydrolysis in the 3rd digit (sulfatase,... 

Figure 11 A possible mechanism for phosphate monoester hydrolysis catalyzed by PPPs. ...

Figure 12 Possible mechanisms for phosphate monoester hydrolysis catalyzed by eukaryotic (a) and prokaryotic (b) PPMs. The representation for eukaryotic PPMs is based on the crystal structure of PP2Ca bound to phosphate (PDB code 1A6Q). In the published structure the phosphate anion is not directly coordinated to the metal ions and it has been modified here to represent a catalytic complex analogous with that implicated by the crystal structure of the homologue MspP bound to phosphate (PDB code 2JFR) see text for details. The octahedral coordination of metals Ml and M2 are completed by bridging carboxylate residues Asp60 in PP2Ca, and Asp35 in MspP (not shown for clarity). Water molecules complete the octahedral coordination at third metal site of the prokaryotic MspP.

The AP-catalyzed phosphate monoester hydrolysis proceeds through a loose transition state with a >10 -fold rate enhancement relative to the rate of the uncatalyzed reaction, whereas phosphate diester and phosphonate monoester hydrolysis proceeds through a tighter, associative transition states with 10 and 10 °-fold rate enhancements, respectively. According to transition state theory, enzymatic rate enhancements arise from preferential stabilization of the transition state relative to the ground state. Consequently, the specificity of an enzyme for a particular reaction depends on its ability to recognize and stabilize... 

Duarte F, Aqvist J, Williams NH, Kamerlin SCL. Resolving apparent conflicts between theoreticA and experimentA models of phosphate monoester hydrolysis. J Am Chem Soc. 2015 137 1081-1093. 

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. 

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