Organophosphorus substrates, hydrolysis

OrganometaUic compounds, of transition metals as catalysts for polymerization of vinyl monomers and olefins, 23 263-325 OrganometaUic transformation, molecular analogs, 38 288, 290-291 Organophosphorus substrates, hydrolysis of, effect of cycloamyloses on, 23 235 Organosilicon compounds, hexacoordinated, 34 155... 

However, the most common and important method of synthesis of chiral non-racemic hydroxy phosphoryl compounds has been the resolution of racemic substrates via a hydrolytic enzyme-promoted acylation of the hydroxy group or hydrolysis of the 0-acyl derivatives, both carried out under kinetic resolution conditions. The first attempts date from the early 1990s and have since been followed by a number of papers describing the use of a variety of enzymes and various types of organophosphorus substrates, differing both by the substituents at phosphorus and by the kind of hydroxy (acetoxy)-containing side chain. 

Other interesting examples of proteases that exhibit promiscuous behavior are proline dipeptidase from Alteromonas sp. JD6.5, whose original activity is to cleave a dipeptide bond with a prolyl residue at the carboxy terminus [121, 122] and aminopeptidase P (AMPP) from E. coli, which is a prohne-specific peptidase that catalyzes the hydrolysis of N-terminal peptide bonds containing a proline residue [123, 124]. Both enzymes exhibit phosphotriesterase activity. This means that they are capable of catalyzing the reaction that does not exist in nature. It is of particular importance, since they can hydrolyze unnatural substrates - triesters of phosphoric acid and diesters of phosphonic acids - such as organophosphorus pesticides or organophosphoms warfare agents (Scheme 5.25) [125]. 

All these observations underscore the potential for application of appropriate OPAs to the destruction of organophosphorus compounds with anticholinesterase activity (Cheng and Calomiris 1996). However, since, hydrolysis results in release of fluoride, the possibility of its subsequent incorporation into organic substrates to produce fluoroacetate and 4-fluorothreonine (Reid et al. 1995) may be worth consideration. 

Organophosphate and carbamate pesticides are potent inhibitors of the enzyme cholinesterase. The inhibition of cholinesterase activity by the pesticide leads to the formation of stable covalent intermediates such as phosphoryl-enzyme complexes, which makes the hydrolysis of the substrate very slow. Both organophosphorus and carbamate pesticides can react with AChE in the same manner because the acetylation of the serine residue at the catalytic center is analogous to phosphorylation and carbamylation. Carbamated enzyme can restore its catalytic activity more rapidly than phosphorylated enzyme [17,42], Kok and Hasirci [43] reported that the total anti-cholinesterase activity of binary pesticide mixtures was lower than the sum of the individual inhibition values. 

A device based on a porous silica substrate used as a Fabry-Perot interferometer has been reported as a sensor for organophosphorus nerve agents. The porous silica is coated with a surfactant and a copper hydrolysis catalyst. The mode of operation... 

The effect of irreversible inhibition of acetylcholinesterase has been used in dendrimer-based electrochemical biosensors for environmental applications. Acetylcholinesterase is a very efficient protein catalyst for the hydrolysis of its physiological substrate acetylcholine. Organophosphorus and carbamic pesticides, heavy metals and detergents exert strong specific... 

Fig. 8.17 A. Acetylcholinesterase normally catalyzes inactivation of the neurotransmitter acetylcholine in a hydrolysis reaction. The active site serine forms a covalent intermediate with a portion of the substrate during the course of the reaction. B. Diisopropyl phosphofluoridate (DFP), the ancestor of current organophosphorus nerve gases and pesticides, inactivates acetylchohnesterase by forming a covalent complex with the active site serine that cannot be hydrolysed by water. The result is that the enzyme cannot carry out its normal reaction, and acetylcholine accumulates.

Organophosphorus hydrolase (OPH, EC 3.1.8.1) is a homodimer with a binuclear metal center. OPH has broad substrate specificity and can hydrolyze organophosphate pesticides such as methyl paradiion, ediyl parathion, paraoxon, chlorpyrifos, coumaphos, cyanophos and diazinoa Table I 9,12-14). The enzymatic hydrolysis rates are 40 - 2450 times faster than chemical hydrolysis at pH 7.0 and the enzyme is reported to be stable at ten ratures of up to 4S-S0°C (3). However, hydrolysis rates varied from very fast for phosphotriesters and phosphothiolester pesticides (P-0 bond) such as paraoxon (ken > 3800s ) and coumaphos (kcat = 800s ) to limited hydrolysis for Diazinon (kcat == 176 s ) and fensulfothion (l a, = 67 s ) (14). 

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