Structure of an insect epsilon class glutathione S-transferase from the malaria vector Anopheles gambiae provides an explanation for the high DDT-detoxifying activity

Wang, Y. J., Qiu, L., Ranson, Hilary ORCID: https://orcid.org/0000-0003-2332-8247, Lumjuan, Nongkran, Hemingway, Janet ORCID: https://orcid.org/0000-0002-3200-7173, Setzer, W. N., Meehan, E. J. and Chen, L. Q. (2008) 'Structure of an insect epsilon class glutathione S-transferase from the malaria vector Anopheles gambiae provides an explanation for the high DDT-detoxifying activity'. Journal of Structural Biology, Vol 164, Issue 2, pp. 228-235.

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Abstract

Glutathione S-transferases (GSTs), a major family of detoxifying enzymes, play a pivotal role in insecticide resistance in insects. In the malaria vector Anopheles gambiae, insect-specific epsilon class GSTs are associated with resistance to the organochlorine insecticide DDT [1,1,1-trichloro-2,2-bis-(p-chloro-phenyl)ethane]. Five of the eight class members have elevated expression levels in a DDT resistant strain. agGSTe2 is considered the most important GST in conferring DDT resistance in A. gambiae, and is the only member of the epsilon class with confirmed DDT-metabolizing activity. A delta class GST from the same species shows marginal DDT-metabolizing activity but the activity of agGSTe2 is approximately 350x higher than the delta class agGST1-6. To investigate its catalytic mechanism and the molecular basis of its unusually high DDT-metabolizing ability, three agGSTe2 crystal structures including one apo form and two binary complex forms with the co-factor glutathione (GSH) or the inhibitor S-hexylglutathione (GTX) have been solved with a resolution up to 1.4 angstrom. The structure of agGSTe2 shows the canonical GST fold with a highly conserved N-domain and a less conserved C-domain. The binding of GSH or GTX does not induce significant conformational changes in the protein. The modeling of DDT into the putative DDT-binding pocket suggests that DDT is likely to be converted to DDE [1,1-dichloro-2,2-bis-(p-chloro-phenyl)ethylene] through an elimination reaction triggered by the nucleophilic attack of the thiolate group of GS(-) on the beta-hydrogen of DDT. The comparison with the less active agGST1-6 provides the structural evidence for its high DDT-detoxifying activity. In short, this is achieved through the inclination of the upper part of H4 helix (H4 '' helix), which brings residues Arg112, Glu116, and Phe120 closer to the GSH-binding site resulting in a more efficient GS(-)-stabilizing hydrogen-bond-network and higher DDT-binding affinity. (C) 2008 Elsevier Inc. All rights reserved.

Item Type:	Article
Uncontrolled Keywords:	aggste2 anopheles gambiae crystal structure ddt resistance glutathione s-transferase malaria heterologous expression crystal-structures resistant strain aedes-aegypti cloning enzyme identification mechanism program defense
Subjects:	QX Parasitology > Insects. Other Parasites > QX 515 Anopheles QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control QX Parasitology > Insects. Other Parasites > QX 650 Insect vectors
Digital Object Identifer (DOI):	https://doi.org/10.1016/j.jsb.2008.08.003
Depositing User:	Users 183 not found.
Date Deposited:	14 Oct 2010 14:49
Last Modified:	17 Dec 2021 11:12
URI:	https://archive.lstmed.ac.uk/id/eprint/658

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