Alleviation of Acute Poisoning of Organophosphates in Humans

Abstract

Acetylcholinesterase (AChE) (EC 3.1.1.7) is the primary cholinesterase belongs to carboxylesterase family . It is an acetylhydrolase, found in many types of conducting tissues. AChE is also found on the red blood cell membranes and blood plasma (EC 3.1.1.8, ChE) [1]. The function of AChE is the termination of ACh at the junctions of the various cholinergic nerve endings with their post-synaptic sites which catalyzes the breakdown of acetylcholine that function as neurotransmitters with very high catalytic activity. The turn over number for AChE has been found to be about 25000 molecules of acetylcholine (ACh) hydrolysed per second [2]. The AChE activity is higher in motor neurons than in sensory neurons [3,4]. AChE exists in multiple molecular forms with different oligomeric assembly but having the same catalytic activities. The enzyme has been reported to be membrane bound [5-7]. The active site of AChE has two sub sites anionic site and esteraticsubsite. The esteraticsubsite contains the catalytic triad of three amino acids: serine 200, histidine 440 and glutamate 327 similar to the triad in other serine proteases except that the glutamate is the third member rather than aspartate, where acetylcholine is hydrolyzed to acetate and choline [8]. The hydrolysis reaction of the carboxyl ester forms an acyl-enzyme and free choline. Then, the acyl-enzyme undergoes nucleophilic attack by a water molecule, assisted by the histidine 440 group, liberating acetic acid and regenerating the free enzyme [9,10]. The mechanism of action of AChE has been elucidated in (Figure 1). The anionic sub site accommodates the positive quaternary amine of acetylcholine and other cationic substrates and inhibitors. The cationic substrates are not bound by interaction of 14 aromatic amino residues [11], which are highly conserved across different species [12]. Among these aromatic amino acids the substitution of tryptophan 84 with alanineresults in a 3000-fold decreased reactivity [13]. During neurotransmission, ACh is released