Structure of an insect δ-class glutathioneS-transferase from a DDT-resistant strain of the malaria vectorAnopheles gambiae

Abstract

Glutathione S-transferases (GSTs) are a major family of detoxification enzymes which possess a wide range of substrate specificities. Most organisms possess many GSTs belonging to multiple classes. Interest in GSTs in insects is focused on their role in insecticide resistance; many resistant insects have elevated levels of GST activity. In the malaria vector Anopheles gambiae, elevated GST levels are associated with resistance to the organochlorine insecticide DDT [1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane]. This mosquito is the source of an insect GST, agGSTd1-6, which metabolizes DDT and is inhibited by a number of pyrethroid insecticides. The crystal structure of agGSTd1-6 in complex with its inhibitor S-hexyl glutathione has been determined and refined at 2.0 A resolution. The structure adopts a classical GST fold and is similar to those of other insect delta-class GSTs, implying a common conjugation mechanism. A structure-based model for the binding of DDT to agGSTd1-6 reveals two subpockets in the hydrophobic binding site (H-site), each accommodating one planar p-chlorophenyl ring.

Modulation ofAnopheles gambiaeEpsilon glutathione transferase activity by plant natural productsin vitro

“…However, the advent of DDT resistant strains of mosquitoes has decreased the effectiveness of this control measure [11]. A DDT resistant strain of A. gambiae has been found to have elevated levels of multiple epsilon class GSTs.…”

“…Elevated GST activity has been detected in strains of insects that are resistant to organophosphates and organochlorines [4,9]. Insect GSTs have been classified into six classes: d, 1, s, u, v, and j [11]. The d and 1-class GSTs have been associated with detoxification of various insecticides [12].…”

“…An gambiae GSTs are of particular interest because of their involvement in resistance to DDT [1,1,1-trichloro-2,2-bis-p(-chlorophenyl)ethane]. DDT was widely used in the 1960s and 1970s to spray in houses as a defence against malaria, but since this period DDT-resistant strains of mosquitoes have arisen [11]. This has led to decreased effectiveness of this control measure.…”

“…Dehydrochlorination of DDT to its non-insecticidal metabolite DDE by AgGSTE2. The two phenyl rings enter into the two pockets of the H-site during the dehydrochlorination reaction ( [11]). …”

Identification, genomic organization, and oxidative stress response of a sigma class glutathione S-transferase gene (AccGSTS1) in the honey bee, Apis cerana cerana

“…Because GST genes play important roles in detoxification pathways and the oxidative stress response, studies on GST resistance have been widely reported in insects, including Drosophila melanogaster Low et al 2007;Sawicki et al 2003;Tang and Tu 1994;Tu and Akgul 2005), Anopheles gambiae (Chen et al 2003;Ding et al 2003Ding et al , 2005Ranson et al 2000Ranson et al , 2001, and Bombyx mori (Yamamoto et al 2006;Yu et al 2008), but information about other important species is rather limited. Honey bees, which serve as an excellent model for social behavior research, are a major plant pollinator and thus play essential roles in agriculture and ecological balance.…”