TY - JOUR
T1 - Molecular action of larvicidal flavonoids on ecdysteroidogenic glutathione S-transferase Noppera-bo in Aedes aegypti
AU - Inaba, Kazue
AU - Ebihara, Kana
AU - Senda, Miki
AU - Yoshino, Ryunosuke
AU - Sakuma, Chisako
AU - Koiwai, Kotaro
AU - Takaya, Daisuke
AU - Watanabe, Chiduru
AU - Watanabe, Akira
AU - Kawashima, Yusuke
AU - Fukuzawa, Kaori
AU - Imamura, Riyo
AU - Kojima, Hirotatsu
AU - Okabe, Takayoshi
AU - Uemura, Nozomi
AU - Kasai, Shinji
AU - Kanuka, Hirotaka
AU - Nishimura, Takashi
AU - Watanabe, Kodai
AU - Inoue, Hideshi
AU - Fujikawa, Yuuta
AU - Honma, Teruki
AU - Hirokawa, Takatsugu
AU - Senda, Toshiya
AU - Niwa, Ryusuke
N1 - Funding Information:
This work was supported in part by a KEK Postgraduate Research Student fellowship to K.I., Japan Society for the Promotion of Sciences KAKENHI (grant numbers 15K14719, 17H01472, and 18K19163) to R.N. and by the Private University Research Branding Project. Additionally, this research was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED, under the Grant Numbers: JP21am0101071, JP21am0101086, JP21am0101113, and JP21am0101114 (Support numbers: 1290, 2145, 2528, and 2966, respectively). This work was carried out by the joint research program of the Institute for Molecular and Cellular Regulation, Gunma University (21020).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Aedes aegypti
KW - Ecdysone
KW - Ecdysteroid
KW - Flavonoid
KW - Glutathione S-transferase
KW - Insect growth regulator
KW - Insecticide
KW - Mosquito
KW - Noppera-bo
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UR - http://www.scopus.com/inward/citedby.url?scp=85125267565&partnerID=8YFLogxK
U2 - 10.1186/s12915-022-01233-2
DO - 10.1186/s12915-022-01233-2
M3 - Article
C2 - 35172816
AN - SCOPUS:85125267565
SN - 1741-7007
VL - 20
JO - BMC Biology
JF - BMC Biology
IS - 1
M1 - 43
ER -
