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, Yujun; Qiu, Li Ping; Ranson, Hilary; Lumjuan, Nongkran; Hemingway, Janet; Setzer, William N.; Meehan, Edward J.; Chen, Liqing

doi:10.1016/j.jsb.2008.08.003

Cited by 70 publications

(100 citation statements)

References 38 publications

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“…17 Protein structure homology modeling relies on the evolutionary relationship between the target and template proteins. 23,24 Therefore, the more similar two sequences are, the closer the corresponding structures can be expected to be and the larger the fraction of the model that can be directly inferred from the template.…”

Section: Methodsmentioning

confidence: 99%

“…1 Increased conformational dynamics has also been proposed to explain the 350-fold higher catalytic efficiency of GSTE2 compared to GSTs from the Delta class in the same species. 14,17 Previous structural and biochemical characterization of the Delta class GSTD4 from A. gambiae has underlined the importance of several residues for catalysis and substrate specificity of the enzyme through structural rearrangements. 18,19 These conformational changes have been postulated to alter the flexibility of the protein, and thus modulate its catalytic aptness.…”

Section: Introductionmentioning

confidence: 99%

“…In this report, we investigate the proposed role of increased conformational dynamics on the biological activity of GSTE variants (GSTE2, AgGSTE2-I114T/F120L and GSTE5) from A. gambiae via molecular dynamics (MD) simulations ( Figure 1). 1,17 MD simulations provide an atomic description of the time-evolution of conformations of a system due to its singular property of probing space and time scales simultaneously. [20][21][22] For this reason, it is a powerful technique to explore conformational transitions of biomolecules at the atomic level.…”

Section: Introductionmentioning

confidence: 99%

“…These findings support the hypothesis that the increase of the conformational dynamics promotes higher DDTase activity of GST Epsilon class isoforms from A. gambiae. 1, 17 We propose a molecular mechanism to explain the effect of GST polymorphisms on DDT-resistance. …”

mentioning

confidence: 99%

“…1, 17 We propose a molecular mechanism to explain the effect of GST polymorphisms on DDT-resistance.…”

mentioning

confidence: 99%

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The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance inAnopheles gambiae

Pontes¹,

Maia²,

Lima³

et al. 2016

Journal of the Brazilian Chemical Society

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Glutathione S-transferases (GSTs) are enzymes capable of metabolizing cytotoxic compounds. The enzyme AgGSTE2, member of epsilon class GSTs (GSTE), is the most important GST conferring resistance to dichloro-diphenyl-trichloroethane (DDT) in Anopheles gambiae. We have investigated the conformational dynamics of three GSTE variants (GSTE2, GSTE2-I114T/F120L, GSTE5) from A. gambiae. Large-scale motions of helices H2 and H4 and conformational transition of the C-terminal governs the opening of the G-site and is expected to affect substrate binding and product release. This structural rearrangement places Glu116 (Glu120 in GSTE5) close of the thiol group of the tripeptide glutathione (GSH) cofactor, making this residue a candidate to act as a base in the activation of DDT. The structural rearrangement is noticeable for AgGSTE2-F120L, which has been shown to confer increased DDT-resistance. The other variants exhibit a more subtle rearrangement. These findings corroborate the hypothesis that the increase of the conformational dynamics of GST Epsilon class isoforms from A. gambiae promotes higher DDTase activity.Keywords: molecular dynamics simulation, evolutional constraint, positive and negative selection, metabolic resistance, malaria vector IntroductionGlutathione transferases (EC 2.5.1.18) are highly promiscuous proteins where broad functional promiscuity co-exists with highly conserved structural fold. Glutathione S-transferases (GSTs) constitute a large family of cytosolic and membrane-bound proteins that catalyze the nucleophilic addition of the tripeptide glutathione (GSH) to a variety of electrophilic toxins and drugs (xenobiotics), leading to their excretion. 1,2 Lately, several other activities have also been associated with GSTs, including steroid and leukotriene biosynthesis, peroxide degradation, doublebond cis-trans isomerization, dehydroascorbate reduction, Michael addition, and noncatalytic ligand binding and transport activity. 3 These polymorphic enzymes belong to supergene families whose members are generated by punctual mutations, gene duplication and alternative splicing. 4 The GST family is subdivided into several classes accordingly to its occurrence in different taxa.The number of isoforms per class varies widely, ranging from one to forty. 4 A single GST isoform is capable of conjugating glutathione to several hydrophobic substrates. Such promiscuity when coupled with the large number of isozymes generates a large range of potential substrates.Insects exhibit at least six classes of GSTs (Sigma, Omega, Theta, Zeta, Delta and Epsilon) with the first four classes present in almost all living organisms. 4,5 The Epsilon and Delta classes are arthropod specific and some members of these classes have been associated to insecticide resistance in culicid vectors. 5,6 The metabolism of toxic compounds in insects is conducted by a series of enzymes from different phases and GSTs act in phase II. GSTs metabolize these compounds in two ways: one has been cited above (through GSH conjugation) and the oth...

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

“…1, 17 We propose a molecular mechanism to explain the effect of GST polymorphisms on DDT-resistance.…”

mentioning

confidence: 99%

See 3 more Smart Citations

The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance inAnopheles gambiae

Pontes¹,

Maia²,

Lima³

et al. 2016

Journal of the Brazilian Chemical Society

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Structure and steroid isomerase activity of Drosophila glutathione transferase E14 essential for ecdysteroid biosynthesis

et al. 2020

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Ecdysteroids are critically important for the formation of the insect exoskeleton. Cholesterol is a precursor of ecdysone and its active form 20-hydroxyecdysone, but some steps in the ecdysteroid biosynthesis pathway remain unknown. An essential requirement of glutathione (GSH) transferase GSTE14 in ecdysteroid biosynthesis has been established in Drosophila melanogaster, but its function is entirely unknown. Here, we have determined the crystal structure of GSTE14 in complex with GSH and investigated the kinetic properties of GSTE14 with alternative substrates. GSTE14 has highranking steroid double-bond isomerase activity, albeit 50-fold lower than the most efficient mammalian GSTs. Corresponding steroid isomerizations are unknown in insects, and their exact physiological role remains to be shown. Nonetheless, the essential enzyme GSTE14 is here demonstrated to be catalytically competent and have a steroid-binding site.

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A novel GSTe2 involved in metamorphosis by regulating 20E signal pathway in Tribolium castaneum

Kim

Song

et al. 2023

Arch Insect Biochem Physiol

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Insect‐specific epsilon glutathion S‐transferases (GSTs) are a class of multifunctional GST superfamily, which play important roles in detoxification of xenobiotic substances. Most research on GSTs has focused on insecticide detoxification and resistance, with little research on other physiological functions. Here, we identified and cloned the novel GSTe2 from Tribolium castaneum (TcGSTe2). Recombinant TcGSTe2 protein was successfully overexpressed in Escherichia coli and purified with affinity purification, which had high ability to catalyze the conjugation of reduced glutathione with 1‐chloro‐2,4‐dinitrobenzene (CDNB). The expression level of TcGSTe2 was significantly decreased after exposure with four insecticides, phoxim, λ‐cyhalothrin, dichlorvos, and carbofuran, in larval stage. Interestingly, RNA interference knockdown of TcGSTe2 caused metamorphosis deficiency in larval and pupal stages by inhibiting the 20E signal pathway. Furthermore, exogenous 20E injection partially rescued this metamorphosis deficiency and also increased the expression levels of 20E downstream response genes. This study illustrated TcGSTe2 plays an important role at metamorphosis beside the insecticide detoxification and resistance in T. castaneum.

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

Cited by 70 publications

References 38 publications

The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance inAnopheles gambiae

The Role of the Conformational Dynamics of Glutathione S-Transferase Epsilon Class on Insecticide Resistance inAnopheles gambiae

Structure and steroid isomerase activity of Drosophila glutathione transferase E14 essential for ecdysteroid biosynthesis

A novel GSTe2 involved in metamorphosis by regulating 20E signal pathway in Tribolium castaneum

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