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

• Published in: Journal of antibiotics Vol. 75; no. 7; pp. 361 - 374
• Main Authors: Abdelhakim, Islam A., Motoyama, Takayuki, Nogawa, Toshihiko, Mahmud, Fauze Bin, Futamura, Yushi, Takahashi, Shunji, Osada, Hiroyuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2022; Springer Nature; Nature Publishing Group
• Subjects: 42/41; 631/92/349; 639/638/60; 639/638/92/349; Aldehyde dehydrogenase; Aldehyde Dehydrogenase - genetics; Aldehydes; Antibiotics; Antimalarial agents; Antimalarials - pharmacology; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Biosynthesis; Biotechnology & Applied Microbiology; Carbon radioisotopes; Cell cycle; Dehydrogenase; Dehydrogenases; Epoxidation; Furans; Fusarium; Fusarium - genetics; Genes; Hydroxylation; Immunology; Life Sciences; Life Sciences & Biomedicine; Malaria; Medicinal Chemistry; Metabolites; Methyltransferase; Microbiology; Mixed Function Oxygenases; Monooxygenase; Organic Chemistry; Pharmacology & Pharmacy; Pyrroles; Science & Technology; RICE BLAST FUNGUS; METABOLITES; OSMOTIC-STRESS RESPONSE; CELL-CYCLE INHIBITOR; ASYMMETRIC TOTAL-SYNTHESIS
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-022-00529-3

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.