Abstract
Current anticholinesterase pesticides were developed during World War II and are toxic to mammals because they target a catalytic serine residue of acetylcholinesterases (AChEs) in insects and in mammals. A sequence analysis of AChEs from 73 species and a three-dimensional model of a malaria-carrying mosquito (Anopheles gambiae) AChE (AgAChE) reported here show that C286 and R339 of AgAChE are conserved at the opening of the active site of AChEs in 17 invertebrate and four insect species, respectively. Both residues are absent in the active site of AChEs of human, monkey, dog, cat, cattle, rabbit, rat, and mouse. The 17 invertebrates include house mosquito, Japanese encephalitis mosquito, African malaria mosquito, German cockroach, Florida lancelet, rice leaf beetle, African bollworm, beet armyworm, codling moth, diamondback moth, domestic silkworm, honey bee, oat or wheat aphid, the greenbug, melon or cotton aphid, green peach aphid, and English grain aphid. The four insects are house mosquito, Japanese encephalitis mosquito, African malaria mosquito, and German cockroach. The discovery of the two invertebrate-specific residues enables the development of effective and safer pesticides that target the residues present only in mosquito AChEs rather than the ubiquitous serine residue, thus potentially offering an effective control of mosquito-borne malaria. Anti-AgAChE pesticides can be designed to interact with R339 and subsequently covalently bond to C286. Such pesticides would be toxic to mosquitoes but not to mammals.
Highlights
Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in mammals and in insects, has long been used as a target for pesticides
It has been reported that a native or engineered cysteine residue near the active site of an enzyme can hook a small molecule that binds, even loosely, at the active site, as long as the cysteine residue is able to react with an eletrophilic group of the molecule [19]
It has been reported that reactive chemicals—which are covalently bonded to an engineered cysteine (H287C) at the peripheral site of mammalian AChEs (Figure 2)—are able to interfere with the substrate binding and subsequently inhibit the enzymes [20,21]
Summary
Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in mammals and in insects, has long been used as a target for pesticides. This enzyme has a deep and narrow active site, the bottom and opening regions of which are known as catalytic and peripheral sites, respectively [1,2]. Current anticholinesterase pesticides for controlling pests, including African malaria-carrying mosquito (Anopheles gambiae), were developed during the World War II era. They react with a serine residue at the catalytic site, disabling the function of AChE. The use of anticholinesterase pesticides has been limited by resistance problems caused by mosquitoes possessing AChE mutants such as the G119S mutant that is insusceptible to current pesticides [4]
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