African Malaria Mosquito Acetylcholinesterase

From Proteopedia

Theoretical Model: The protein structure described on this page was determined theoretically, and hence should be interpreted with caution.

Model: Acetylcholinesterase of the African Malaria Mosquito - by Yuan-Ping Pang

Unlike mammals, many disease-transmitting or crop-pest insects have two AChE genes (AP and AO) ^{[1][2][3][4][5][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][8][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]}. 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 model 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].

References & Notes

1. ↑ J.-R. Gao, K.Y. Zhu, Increased expression of an acetylcholinesterase gene may confer organophosphate resistance in the greenbug, Schizaphis graminum (Homoptera: Aphididae), Pesticide Biochemistry and Physiology 73(3) (2002) 164-173.
2. ↑ Gao JR, Kambhampati S, Zhu KY (2002) Molecular cloning and characterization of a greenbug (Schizaphis graminum) cDNA encoding acetylcholinesterase possibly evolved from a duplicate gene lineage. Insect Biochem Mol Biol 32: 765-775.
3. ↑ Weill M, Fort P, Berthomieu A, Dubois MP, Pasteur N, et al. (2002) A novel acetylcholinesterase gene in mosquitoes codes for the insecticide target and is non-homologous to the ace gene in Drosophila. Proc Biol Sci 269: 2007-2016.
4. ↑ Baek JH, Kim JI, Lee D-W, Chung BK, Miyata T, et al. (2005) Identification and characterization of ace1-type acetylcholinesterase likely associated with organophosphate resistance in Plutella xylostella. Pestic Biochem Physiol 81: 164-175.
5. ↑ Kono Y, Tomita T (2006) Amino acid substitutions conferring insecticide insensitivity in Ace-paralogous acetylcholinesterase. Pestic Biochem Physiol 85: 123-132.
6. ↑ Mamiya A, Ishikawa Y, Kono Y (1997) Acetylcholinesterase in insecticide resistant Culex tritaeniorhynchus: characteristics accompanying insensitivity to inhibitors. Appl Entomol Zool 32: 37-44.
7. ↑ Pezzementi L, Rowland M, Wolfe M, Tsigelny I (2006) Inactivation of an invertebrate acetylcholinesterase by sulfhydryl reagents: the roles of two cysteines in the catalytic gorge of the enzyme. Invert Neurosci 6: 47-55.
8. ↑ ^{8.0 8.1 8.2} Y.-P. Pang, Novel Acetylcholinesterase Target Site for Malaria Mosquito Control, PLoS ONE 1 (2006) e58. Paper
9. ↑ Pang YP. Species marker for developing novel and safe pesticides. Bioorg Med Chem Lett. 2007 Jan 1;17(1):197-9. Epub 2006 Oct 12. PMID:17046256 doi:10.1016/j.bmcl.2006.09.073
10. ↑ ^{10.0 10.1} Y.-P. Pang, S.K. Singh, Y. Gao, T.L. Lassiter, R.K. Mishra, K.Y. Zhu, S. Brimijoin, Selective and Irreversible Inhibitors of Aphid Acetylcholinesterases: Steps Toward Human-Safe Insecticides, PLoS ONE 4 (2009) e4349. Paper
11. ↑ ^{11.0 11.1} Pang Y-P, Ekstrom F, Polsinelli GA, Gao Y, Rana S, et al. (2009) Selective and irreversible inhibitors of mosquito acetylcholinesterases for controlling malaria and other mosquito-borne diseases. Paper
12. ↑ The model of AP-AgAChE in its bound state was released at Mayo Research Protein Structure Prediction on Dec 12, 2009
13. ↑ Per the Protein Data Bank record, 2AZG was deposited to Protein Data Bank on Sept 5, 2005, eight months prior to the online publication of reference 7.
14. ↑ This author thanks Professor Joel L. Sussman and his colleagues for their creation and maintenance of PROTEOPEDIA that permits archiving computational models of macromolecular structures and assessment of protein structure prediction made prior to experimental structures.

Download the model coordinates of AChE of the African Malaria Mosquito (PDB format)