Bimolecular inhibition constant

Organophosphorus insecticides give very stable acylated enzymes (AE does not hydrolyze because +3 is very small). The potency of an inhibitor is much determined by how stable the Michaelis complex is (as expressed by the size of Kd) and how fast the acylated enzyme is formed (expressed as the size of k+2). A constant including Kd and k+2, called the bimolecular inhibition constant, is often used to describe the strength of an inhibitor because it is very easy to determine experimentally and it tells us how potent the inhibitor is ... 

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... 

Figure 5. Relationship between the bimolecular Inhibition reaction constant (kj) of substituted phenyl N-methylcarbamates and the inhibition dissociation constant (Kj) of the corresponding N-methyl N-methoxycarbamates in their reaction with house fly acetylcholinesterase, k Values were recalculated from (42) and Kj values were from (41).

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

Deprotonation reaction of dipyrrole 179 was studied by nanosecond laser photolysis. The bimolecular rate constants of proton transfer to heterocyclic bases were determined. The inhibiting of the radical cation reaction by bases occurs during the radical cation formation (09CHE554). 

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). 

The overall progress of the reaction from E-OH and inhibitor to phosphonylated enzyme is characterized by the bimolecular rate constant of inhibition, ki. This important measure of inhibitory potency is determined by measuring the activity remaining as a function of time of preincubation with various concentrations of inhibitor. The substrate is... 

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...

In general, resistant acetylcholinesterases are less sensitive as indicated by a smaller bimolecular reaction constant, kj, for phosphorylation of the active site. In our studies of methyl parathion resistant tobacco budworm larvae, lots of ten larval nervous systems were homogenized and kj was determined (22). We observed 25-fold less sensitivity to inhibition to methyl paraoxon in the resistant strain (Table IV). 

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

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. 

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