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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


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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  1. Kakeya H. et al. Lucilactaene, a new cell cycle inhibitor in p53-transfectedcancer cells, produced by a Fusarium sp. J Antibiot. 2001;54:850–4.

    Article  CAS  Google Scholar 

  2. Sugawara T, Shinonaga H, Simura H, Yoshikawa R, Yamamoto K. Jpn. Kokai Tokkyo Koho 319289. 1996.

  3. Hayashi Y, Yamaguchi J, Shoji M. The diastereoselective asymmetric total synthesis of NG-391, a neuronal cell-protecting molecule. Tetrahedron. 2002;58:9839–46.

    Article  CAS  Google Scholar 

  4. Coleman RS, Walczak MC, Campbell EL. Total synthesis of Lucilactaene, a cell cycle inhibitor active in p53-inactive cells. J Am Chem Soc. 2005;127:16038–9.

    Article  CAS  Google Scholar 

  5. Yamaguchi J. et al. Determination by asymmetric total synthesis of the absolute configuration of lucilactaene, a cell-cycle inhibitor in p53-transfected cancer cells. Angew Chem. 2005;44:3110–5.

    Article  CAS  Google Scholar 

  6. Kato S. et al. Biosynthetic gene cluster identification and biological activity of lucilactaene from Fusarium sp. RK97-94. Biosci. Biotechnol Biochem. 2020;84:1303–7.

    Article  CAS  Google Scholar 

  7. Abdelhakim IA. et al. Dihydrolucilactaene, a potent antimalarial compound from Fusarium sp. RK97-94. J Nat Prod. 2022;85:63–9.

    Article  Google Scholar 

  8. Niehaus EM. et al. Genetic manipulation of the Fusarium fujikuroi fusarin gene cluster yields insight into the complex regulation and fusarin biosynthetic pathway. Chem Biol. 2013;20:1055–66.

    Article  CAS  Google Scholar 

  9. Kleigrewe K, Niehaus EM, Wiemann P, Tudzynski B, Humpf HU. New approach via gene knockout and single-step chemical reaction for the synthesis of isotopically labeled fusarin C as an internal standard for the analysis of this Fusarium mycotoxin in food and feed samples. J Agric Food Chem. 2012;60:8350–5.

    Article  CAS  Google Scholar 

  10. Yang Q. et al. Characterization of a carboxyl methyltransferase in Fusarium graminearum provides insights into the biosynthesis of fusarin A. Org Biomol Chem. 2021;19:6638–43.

    Article  CAS  Google Scholar 

  11. Krasnoff SB. et al. Production of mutagenic metabolites by Metarhizium anisopliae. J Agric Food Chem. 2006;54:7083–8.

    Article  CAS  Google Scholar 

  12. Kyekyeku JO. et al. Antibacterial secondary metabolites from an endophytic fungus, Fusarium solani JK10. Fitoterapia. 2017;119:108–14.

    Article  CAS  Google Scholar 

  13. Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. Cold Spring Harbor Laboratory Press; Cold Spring Harbor, New York, 1989.

  14. De Groot MJA, Bundock P, Hooykaas PJJ, Beijersbergen AGM, Chapman JW. Agrobacterium tumefaciens-mediated transformation of filamentous fungi. Nat Biotechnol. 1998;16:839–42.

    Article  Google Scholar 

  15. Motoyama T, Ochiai N, Morita M, Iida Y, Usami R, Kudo T. Involvement of putative response regulator genes of the rice blast fungus Magnaporthe oryzae in osmotic stress response, fungicide action, and pathogenicity. Curr Genet. 2008;54:185–95.

    Article  CAS  Google Scholar 

  16. Motoyama T, Hayashi T, Hirota H, Ueki M, Osada H. Terpendole E, a kinesin Eg5 Inhibitor, is a key biosynthetic intermediate of indole-diterpenes in the producing fungus Chaunopycnis alba. Chem Biol. 2012;19:1611–9.

    Article  CAS  Google Scholar 

  17. Motoyama T. et al. A two-component histidine kinase of the rice blast fungus is involved in osmotic stress response and fungicide action. Fungal Genet Biol. 2005;42:200–12.

    Article  CAS  Google Scholar 

  18. Lim CL. et al. RK-1355A and B, novel quinomycin derivatives isolated from a microbial metabolites fraction library based on NPPlot screening. J Antibiot. 2014;67:323–9.

    Article  CAS  Google Scholar 

  19. Nogawa T. et al. Opantimycin A, a new metabolite isolated from Streptomyces sp. RK88-1355. J Antibiot. 2017;70:222–5.

    Article  CAS  Google Scholar 

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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).

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