Molecular action of larvicidal flavonoids on ecdysteroidogenic glutathione S-transferase Noppera-bo in Aedes aegypti

Abstract

Background Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment. However, the mode of mosquito larvicidal action of flavonoids has not been elucidated. Results Here, we report that several flavonoids, including daidzein, inhibit the activity of glutathione S-transferase Noppera-bo (Nobo), an enzyme used for the biosynthesis of the insect steroid hormone ecdysone, in the yellow fever mosquito Aedes aegypti. The crystal structure of the Nobo protein of Ae. aegypti (AeNobo) complexed with the flavonoids and its molecular dynamics simulation revealed that Glu113 forms a hydrogen bond with the flavonoid inhibitors. Consistent with this observation, substitution of Glu113 with Ala drastically reduced the inhibitory activity of the flavonoids against AeNobo. Among the identified flavonoid-type inhibitors, desmethylglycitein (4′,6,7-trihydroxyisoflavone) exhibited the highest inhibitory activity in vitro. Moreover, the inhibitory activities of the flavonoids correlated with the larvicidal activity, as desmethylglycitein suppressed Ae. aegypti larval development more efficiently than daidzein. Conclusion Our study demonstrates the mode of action of flavonoids on the Ae. aegypti Nobo protein at the atomic, enzymatic, and organismal levels.

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

“…While the function of downregulated GSTs by insecticide treatment could be broadly assumed into two categories. One is the involvement in the other physiological functions, such as the anti‐apotosis function (X. Y. Chen et al, 2015) and metamorphosis function (Inaba et al, 2022); The other is the participation in physiological importance during insecticide treatment, such as compensation for GSH overconsumption due to upregulated GSTs (Qin et al, 2014), regulation of virus‐response cell transporters (Noland et al, 2013; Sun et al, 2020), and binding of redundant components to the enzyme active site (Liao et al, 2016). In this sense, TcGSTe2 could be participated in the maintenance of GST equilibrium during pesticide treatment or other biological functions rather than in pesticide detoxification.…”

Endophytic Fungi Fusarium Equiseti EF2 Isolated from Leucas Aspera: A Novel Biocontrol Agent Against Culex Sp

“…Alkaloids from the plant extract of Evodia rutaecarpa were previously identified to possess mosquito larvicidal activity against Aedes aegypti 51 . Similarly, several flavonoids were known to possess antilarval activity against Aedes aegypti and their mechanisms were also understood 52 . Acenaphthene has been described as a pesticide belonging to the polycyclic aromatic hydrocarbon group of compounds 53,54 .…”

Compounds Inhibiting Noppera-bo, a Glutathione S-transferase Involved in Insect Ecdysteroid Biosynthesis: Novel Insect Growth Regulators

“…GSTs are also used as tags to target proteins in genetic engineering, facilitating mass culture and purification of soluble recombinant proteins using an Escherichia coli expression system [ 64 , 65 , 66 ]. This is also the case for Nobo, as recombinant Nobo proteins can be easily produced by the E. coli expression system and purified using a commercially available conventional GSH column and gel-filtration chromatography [ 67 , 68 , 69 ]. Moreover, a high-throughput in vitro Nobo enzyme activity assay system has been established, which is optimal for screening inhibitors [ 67 ].…”

“…A high-throughput screening was conducted using 3,4-DNADCF with DmNobo recombinant proteins and a library of 9600 small-molecule compounds to identify inhibitors of DmNobo [ 69 ], and several inhibitors were identified [ 68 , 69 , 74 ]. Interestingly, these inhibitors included three steroid compounds, one of which was the mammalian steroid hormone 17 β-Estradiol (EST) [ 67 ].…”