African Malaria Mosquito Acetylcholinesterase
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Joel L. Sussman (Talk | contribs)
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Revision as of 08:21, 15 December 2009
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Model: Bound Acetylcholinesterase (African Malaria Mosquito) Inhibitor Complex - by Yuan-Ping Pang
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Unlike mammals, many disease-transmitting or crop-pest insects have two AChE genes (AP and AO) [1-6]. Interestingly, a free cysteine (Cys) residue, for example, Cys286 of AP-AChE in Anopheles gambiae sensu stricto (AP-AgAChE), is present at the entrance to the active site of insect AP-AChEs but not at that of AO-AChEs and AChEs from mammals, birds, and fish [7-9]. Mosquitoes have an additional arginine residue (Arg339 of AP-AgAChE) at the rim of the AP-AChE active site that appears to be genus-specific [8]. Methanethiosulfonate-containing molecules designed to target the active-site Cys residue reportedly inhibited irreversibly most AChE activity extracted from aphids, the African malaria mosquito, the yellow fever mosquito and the northern house mosquito, while an identical exposure caused no effect on the human AChE [10,11]. Most recent studies showed that the same Cys-targeting molecules irreversibly inhibited most AChE activity extracted from cockroaches, flour beetles, the bed bug and a wasp [manuscript under review]. The irreversible inhibition is primarily caused by the formation of a disulfide bond between the inhibitor and the Cys residue as evident from the reversal of inhibition by 2-mercaptoethanol [10,11]. These results suggest that AP-AChE is a viable target for developing insect-selective pesticides to control crop damage and disease vectors and to alleviate resistance problems of current insecticides with reduced toxicity toward non-target species. The coordinates of AP-AgAChE in its bound state [12] is refined from a published computer model (PDB code: 2AZG) [8,13] using a modified AMBER force field [to be published] and might be useful for structure-based design of anti-malaria agents [14].
