Bimolecular rate constants for inhibition

Acetylcholinesterase bimolecular rate constants for inhibition by organophosphates and carbamate, 53r consequences of existence of isoenzymes in insects, 54... 

Table 10.5 Bimolecular rate constants for the inhibition of acetylcholinesterase by carbamate and organophosphorus insecticides in fall armyworm adults...

In a homologous series of OP compounds, increasing potency for AChE inhibition and cholinergic toxicity correlates with decreasing potency for NTE inhibition and OPIDN. The relative inhibitory potency (RIP) of an OP compound or its active metabolite for NTE versus AChE in vitro can be used as a convenient index of the probable neuropathic potential of the compound. A commonly used measure of inhibitory potency is the IC50, the concentration required to inhibit 50% of the enzyme activity under a standardized set of reaction conditions and time of incubation of the inhibitor with the enzyme preparation. A better measure of inhibitory potency is the bimolecular rate constant of inhibition, ki. When... 

GB, GD, and VX to determine the in vitro mass balance of these OPs. They developed a mathematically based toxicokinetic model for the estimation of the upper limit of Hu BChE dose required for protection against OP toxicity. The model addressed the relationship between the Hu BChE dose needed to maintain 30% of residual red blood cell (RBC) AChE activity and other parameters (level and duration of OP exposure, bimolecular rate constants of inhibition of Hu AChE and Hu BChE by OPs, and time elapsed from enzyme administration). They validated the Hu BChE dose by in vitro experiments and data from published human studies (Ashani et al., 1998 Ashani and Pistinner, 2004). The proposed model suggested that the upper limit doses of 134, 115, and 249 mg/kg of Hu BChE were sufficient to protect RBC AChE above 30% following a challenge with 1 X LD50 of VX, GD, and GB, respectively. 

Table 2. Bimolecular rate constants for acetylcholinesterase inhibition by organophosphates and a carbamate in resistant (R) and susceptible (S) insects...

Since the enzyme is likely attached to the polymer at multiple points and therefore becomes partially distorted, it is not unexpected that the values for the immobilized ChE and OPH were about 10-fold greater than for the corresponding soluble enzyme, but the combined effects on affinity for substrate and k j resulted in approximately a 20- to 50-fold decrease in acylation (k. (/K ). Yet there was no observed shift in the pH profile of the enzymes, and, more important, the bimolecular rate constants for the inhibition of AChE-sponge and BChE-sponge and the soluble enzymes by MEPQ showed no significant difference between soluble and covalently bound enzymes. Therefore, the OP interacts similarly with soluble and immobilized ChE. 

The bimolecular rate constant for the condensation reaction 13 1 low relative to the rate constant for collision between C.F and C2F. Approximately one collision In fifty leads to the formation of products different from the reactants. In the discussion below of condensation reactions In partially fluorl-nated ethylenes, it will be shown that the rearrangement j whlch Is necessary for methyl radical elimination from a C (H,F)g complex is substantially Inhibited by the presence of F-atoms In the complex. This would explain the fact that the rate constants of these reaction are considerably lower, and also more dependent on the Internal energy content of the reactants as compared to the C2H - C2H reaction pair (, ]J). 

In the first group of studies, involving kinetic inhibition studies, comparisons of the uilibrium (K ), phosphorylation (IC), and inhibition constant (K.) for the inhibition of electric eel and human erythrocyte AChE by ANTX-A(S) and DFP were done (Table II). From Table II it is seen that ANTX- A(S) has a higher affinity for human erythrocyte AChE (K =0.253 fiM) than electric eel AChE (K j=3.67 aM). AN DC-A(S) also shows greater affinity for AChE than DFP (K =300 fiM). And finally the bimolecular rate constant, Kj, which indicates the overall rate of reaction, shows AChE is more sensitive toward inhibition by ANTX-A(S) (Kj=1.36 pM- min- ) than DFP (K, = 0.033 /iM- min ). These studies add information to the comparative activity of ANTX-A(S) and other irreversible AChE inhibitors but do not show the site of inhibition. 

Pulse radiolysis has been used to measure the bimolecular rate constants of the electron transfer reaction for substituted 2- and 5-nitroimidazoles of interest as antiprotozoal drugs and radiosensitizers [951], The mechanism of inhibition of... 

In equation (1) K y is referred to as the Stern-Volmer constant Equation (1) applies when a quencher inhibits either a photochemical reaction or a photophysical process by a single reaction. <1>° and M° are the quantum yield and emission intensity (radiant exitance), respectively, in the absence of the quencher Q, while <1> and M are the same quantities in the presence of the different concentrations of Q. In the case of dynamic quenching the constant K y is the product of the true quenching constant kq and the excited state lifetime, t°, in the absence of quencher, kq is the bimolecular reaction rate constant for the elementary reaction of the excited state with the particular quencher Q. Equation (1) can therefore be replaced by the expression (2)... 

The potency of the anticholinesterase activity of nerve agents and other organophosphates is expressed by the bimolecular rate constant (k ) for the reaction of the phosphate compound with the enzyme and by the molar concentration causing 50% inhibition of the enzyme (150). The relationship between I50 and k as a function of time (t) is expressed by the following equation (Eto, 1974) ... 

Interaction of CarbE with nerve agents follows a kinetic of first order characterized by inhibition of CarbE at the active site serine residue described by a bimolecular rate constant, ki (Maxwell and Brecht, 2001). For noncharged nerve agents (e.g. sarin and soman) the ki of rat serum CarbE was found to be >10 M min whereas cationic substrates (e.g. VX) are converted with poor reactivity (ki < 10" M min ). This specificity is explained by the electrostatic characteristics of the large active site containing only a few cation-II bonding and anionic residues (Maxwell and Brecht, 2001 Satoh and Hosokawa, 2006). 

Since the overall rate constant for the reaction kp and the rate constant for the reaction in the absence of micelles klt are readily obtained from kinetic data, a plot of 1/( o — kp) versus [1/(C — CMC)], which should be a straight line with slope = N/K(ko — km) and intercept = l/( o — km), allows the calculation of km, the rate constant for the substrate complexed with the micelle, and K, the binding constant of the substrate to the micelle. This treatment is also applicable to bimolecular micelle-inhibited reactions in which one reagent is excluded from the micelle, for example, by electrostatic repulsion between an ionic reagent and a similarly charged micelle (Menger, 1967). Quantitative treatment of more complex reactions and some of the problems involved has been discussed by Bunton (1979). 

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