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Isolation of new lucilactaene derivatives from P450 monooxygenase and aldehyde dehydrogenase knockout Fusarium sp. RK97-94 strains and their biological activities

Abstract

Fusarium sp. RK97-94 is a producer of potent antimalarial compounds such as lucilactaene and its derivatives. The biosynthetic gene cluster of lucilactaene was identified but only a knockout mutant of methyltransferase (luc1) was reported in previous papers. Herein, we report on isolation and identification of prelucilactaene G (1), and prelucilactaene H (2) from the aldehyde dehydrogenase knockout strain (∆luc3) culture broth, as well as prelucilactaene A (3), prelucilactaene B (4), and two isomeric mixtures of prelucilactaene E (5) and prelucilactaene F (6), from the P450 monooxygenase knockout strain (∆luc2) culture broth. Our data, unlike the previous ones, suggest the involvement of the aldehyde dehydrogenase (Luc3) in lucilactaene biosynthesis, and support the involvement of the P450 monooxygenase (Luc2) in C-20 hydroxylation rather than C-13–C-14 epoxidation or C-15 hydroxylation. Isolated compounds displayed moderate to strong antimalarial activities, and the structure–activity relationship of lucilactaene derivatives was examined.

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Acknowledgements

This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI A) (20H00416, 21H04720), Grants-in-Aid for Scientific Research on Innovative Areas 17H0642, as well as a grant from the Egypt-Japan Education Partnership (EJEP) fund, which is administered by the Japan International Cooperation Agency (JICA) in collaboration with the Egyptian Ministry of Higher Education (MOHE)-Cultural Affairs and Missions Sector. We would like to thank Dr. Takeshi Shimizu for his support in structure elucidation. We are indebted to Ms. Harumi Aono, Ms Emiko Sanada, Dr. Motoko Uchida, Dr. Rachael A. Uson-Lopez, and Ms. Keiko Watanabe (RIKEN) for their support in biological activity tests.

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IAA performed the LC–MS analysis, purification, structure elucidation and feeding of the isolated compounds. TN performed LC–MS/MS analysis. FBM and YF performed the bioactivity assays. IAA, TM, ST, and HO designed the research. IAA and TM wrote the paper.

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Correspondence to Hiroyuki Osada.

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Abdelhakim, I.A., Motoyama, T., Nogawa, T. et al. Isolation of new lucilactaene derivatives from P450 monooxygenase and aldehyde dehydrogenase knockout Fusarium sp. RK97-94 strains and their biological activities. J Antibiot 75, 361–374 (2022). https://doi.org/10.1038/s41429-022-00529-3

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