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Novel acetylcholinesterase target site for malaria mosquito control.

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.

SUBMITTER: Pang YP

PROVIDER: S-EPMC1762403 | biostudies-literature | 2006 Dec

REPOSITORIES: biostudies-literature

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Novel acetylcholinesterase target site for malaria mosquito control.

Pang Yuan-Ping YP

PloS one 20061220

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, respec ...[more]

PMID: 17183688

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Project description:BACKGROUND:Anopheles stephensi mitochondrial malic enzyme (ME) emerged as having a relevant role in the provision of pyruvate for the Krebs' cycle because inhibition of this enzyme results in the complete abrogation of oxygen uptake by mitochondria. Therefore, the identification of ME in mitochondria from immortalized A. stephensi (ASE) cells and the investigation of the stereoselectivity of malate analogues are relevant in understanding the physiological role of ME in cells of this important malaria parasite vector and its potential as a possible novel target for insecticide development. METHODS:To characterize the mitochondrial ME from immortalized ASE cells (Mos. 43; ASE), mass spectrometry analyses of trypsin fragments of ME, genomic sequence analysis and biochemical assays were performed to identify the enzyme and evaluate its activity in terms of cofactor dependency and inhibitor preference. RESULTS:The encoding gene sequence and primary sequences of several peptides from mitochondrial ME were found to be highly homologous to the mitochondrial ME from Anopheles gambiae (98%) and 59% homologous to the mitochondrial NADP+-dependent ME isoform from Homo sapiens. Measurements of ME activity in mosquito mitochondria isolated from ASE cells showed that (i) Vmax with NAD+ was 3-fold higher than that with NADP+, (ii) addition of Mg2+ or Mn2+ increased the Vmax by 9- to 21-fold, with Mn2+ 2.3-fold more effective than Mg2+, (iii) succinate and fumarate increased the activity by 2- and 5-fold, respectively, at sub-saturating concentrations of malate, (iv) among the analogs of L-malate tested as inhibitors of the NAD+-dependent ME catalyzed reaction, small (2- to 3-carbons) organic diacids carrying a 2-hydroxyl/keto group behaved as the most potent inhibitors of ME activity (e.g., oxaloacetate, tartronic acid and oxalate). CONCLUSIONS:The biochemical characterization of Anopheles stephensi ME is of critical relevance given its important role in bioenergetics, suggesting that it is a suitable target for insecticide development.

Project description:BackgroundThere is a global consensus that new intervention tools are needed for the final steps toward malaria elimination/eradication. In a recent study in Burkina Faso, the Lehmann Funnel Entry Trap (LFET) has shown promising results in the reduction of mosquito densities, even in areas where insecticide resistance is as high as 80%. The LFET requires no chemicals and is self-operated. However, one of the issues with the original LFET is the size of the funnel, which often occupies too much space within users' homes. Here, the performance of three new, smaller-sized LFET prototypes that combine a screening and killing effect on mosquitoes was assessed.MethodsThe study was carried out over three months during the rainy season in low and high malaria vector density sites, Soumousso and Vallée du Kou, respectively. The original LFET (or 'Prototype 1'/'P1') was modified to produce three new prototypes, which were referred to as prototype 2 ('the Medium' or 'P2'), prototype 3 (P3) and prototype 4 (P4). Each of the new prototypes was tested on eight days per month over the three-month period to assess their effectiveness in trapping and killing mosquitoes entering houses through the windows compared to the original LFET.ResultsOverall, 78,435 mosquitoes (mainly Anopheles gambiae sensu lato) were collected in the two study sites, both in the traps and in the houses. A total of 56,430 (72%) mosquitoes were collected from the traps. In Vallée du Kou, the original LFET caught a greater number of mosquitoes than the medium (prototype 2), whereas no difference was observed between the other new prototypes (3 and 4) and the medium. In Soumousso, both the original and medium LFETs collected significantly greater numbers of mosquitoes compared to prototypes 3 and 4.ConclusionThis study has shown that the new LFET prototypes are effective in trapping mosquitoes in high mosquito density settings. A large-scale study with one of the prototypes will be needed to assess community acceptance of the traps and their ability to control malaria vectors.

Project description:BackgroundResistance in malaria vectors to pyrethroids, the most widely used class of insecticides for malaria vector control, threatens the continued efficacy of vector control tools. Target-site resistance is an important genetic resistance mechanism caused by mutations in the voltage-gated sodium channel (Vgsc) gene that encodes the pyrethroid target-site. Understanding the geographic distribution of target-site resistance, and temporal trends across different vector species, can inform strategic deployment of vector control tools.ResultsWe develop a Bayesian statistical spatiotemporal model to interpret species-specific trends in the frequency of the most common resistance mutations, Vgsc-995S and Vgsc-995F, in three major malaria vector species Anopheles gambiae, An. coluzzii, and An. arabiensis over the period 2005-2017. The models are informed by 2418 observations of the frequency of each mutation in field sampled mosquitoes collected from 27 countries spanning western and eastern regions of Africa. For nine selected countries, we develop annual predictive maps which reveal geographically structured patterns of spread of each mutation at regional and continental scales. The results show associations, as well as stark differences, in spread dynamics of the two mutations across the three vector species. The coverage of ITNs was an influential predictor of Vgsc allele frequencies, with modelled relationships between ITN coverage and allele frequencies varying across species and geographic regions. We found that our mapped Vgsc allele frequencies are a significant partial predictor of phenotypic resistance to the pyrethroid deltamethrin in An. gambiae complex populations.ConclusionsOur predictive maps show how spatiotemporal trends in insecticide target-site resistance mechanisms in African An. gambiae vary across individual vector species and geographic regions. Molecular surveillance of resistance mechanisms will help to predict resistance phenotypes and track their spread.

Dataset Information

Novel acetylcholinesterase target site for malaria mosquito control.

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Novel acetylcholinesterase target site for malaria mosquito control.

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