Functional characterization of the biosynthesis of radicicol, an Hsp90 inhibitor resorcylic acid lactone from Chaetomium chiversii.
Fungal polyketides with the resorcylic acid lactone (RAL) scaffold are of interest for growth stimulation, the treatment of cancer, and neurodegenerative diseases. The RAL radicicol is a nanomolar inhibitor of the chaperone Hsp90, whose repression leads to a combinatorial blockade of cancer-causing pathways. Clustered genes for radicicol biosynthesis were identified and functionally characterized from the endophytic fungus Chaetomium chiversii, and compared to recently described RAL biosynthetic gene clusters. Radicicol production is abolished upon targeted inactivation of a putative cluster-specific regulator, or either of the two polyketide synthases that are predicted to collectively synthesize the radicicol polyketide core. Genomic evidence supports the existence of flavin-dependent halogenases in fungi: inactivation of such a putative halogenase from the C. chiversii radicicol locus yields dechloro-radicicol (monocillin I). Inactivation of a cytochrome P450 epoxidase furnishes pochonin D, a deepoxy-dihydro radicicol analog.
Wang
Shuhao
S
Southwest Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, The University of Arizona, 250 E. Valencia Road, Tucson, AZ 85706-6800, USA.
Xu
Yuquan
Y
Maine
Erin A
EA
Wijeratne
E M Kithsiri
EM
Espinosa-Artiles
Patricia
P
Gunatilaka
A A Leslie
AA
Molnár
István
I
D002597:Chaetomium / Q000737:chemistry* / Q000235:genetics*; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D007783:Lactones / Q000737:chemistry / Q000378:metabolism; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008954:Models, Biological; D015394:Molecular Structure; D005810:Multigene Family; D015025:Zearalenone / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; C444505:monocillin I; C502130:pochonin D; D015025:Zearalenone; C035359:monorden