TY - JOUR
T1 - Functional Characterization of the Biosynthesis of Radicicol, an Hsp90 Inhibitor Resorcylic Acid Lactone from Chaetomium chiversii
AU - Wang, Shuhao
AU - Xu, Yuquan
AU - Maine, Erin A.
AU - Wijeratne, E. M.Kithsiri
AU - Espinosa-Artiles, Patricia
AU - Gunatilaka, A. A.Leslie
AU - Molnár, István
N1 - Funding Information:
Financial support was provided by startup funds to I.M. from the College of Agriculture and Life Sciences and the Bio5 Institute of the University of Arizona, and by the American Cancer Society. S.W. was supported by the Chinese Academy of Sciences. FTICR-MS service was provided by A. Somogyi at the University of Arizona. Li Chen and Michele Garsha are acknowledged for technical assistance.
PY - 2008/12/22
Y1 - 2008/12/22
N2 - 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.
AB - 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.
KW - CHEMBIO
UR - http://www.scopus.com/inward/record.url?scp=57649230837&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2008.10.006
DO - 10.1016/j.chembiol.2008.10.006
M3 - Article
C2 - 19101477
AN - SCOPUS:57649230837
SN - 1074-5521
VL - 15
SP - 1328
EP - 1338
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 12
ER -
