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

BMC Biology

Daisuke Takaya¹  Chiduru Watanabe¹  Teruki Honma¹  Akira Watanabe²  Nozomi Uemura³  Shinji Kasai³  Chisako Sakuma⁴  Hirotaka Kanuka⁴  Riyo Imamura⁵  Takayoshi Okabe⁵  Hirotatsu Kojima⁵  Kazue Inaba⁶  Takashi Nishimura⁷  Kodai Watanabe⁸  Hideshi Inoue⁸  Yuuta Fujikawa⁸  Yusuke Kawashima⁹  Kaori Fukuzawa⁹  Miki Senda^1,10  Ryusuke Niwa^1,10  Kana Ebihara^1,10  Toshiya Senda^1,10  Kotaro Koiwai^1,10  Takatsugu Hirokawa^1,11  Ryunosuke Yoshino^1,11 

[1] Center for Biosystems Dynamics Research, RIKEN;Degree Programs in Life and Earth Sciences, Graduate School of Science and Technology, University of Tsukuba;Department of Medical Entomology, National Institute of Infectious Diseases;Department of Tropical Medicine, Center for Medical Entomology, The Jikei University School of Medicine;Drug Discovery Initiative, The University of Tokyo;Graduate School of Life and Environmental Sciences, University of Tsukuba;Institute for Molecular and Cellular Regulation, Gunma University;School of Life Sciences, Tokyo University of Pharmacy and Life Sciences;School of Pharmacy and Pharmaceutical Sciences, Hoshi University;Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK);Transborder Medical Research Center, University of Tsukuba;

关键词: Aedes aegypti;    Ecdysone;    Ecdysteroid;    Flavonoid;    Glutathione S-transferase;    Insect growth regulator;   

DOI  :  10.1186/s12915-022-01233-2

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown