Functional Characterization of the Biosynthesis of Radicicol, an Hsp90 Inhibitor Resorcylic Acid Lactone from Chaetomium chiversii

Shuhao Wang; Yuquan Xu; Erin A. Maine; E. M.Kithsiri Wijeratne; Patricia Espinosa-Artiles; A. A.Leslie Gunatilaka; István Molnár

doi:10.1016/j.chembiol.2008.10.006

Functional Characterization of the Biosynthesis of Radicicol, an Hsp90 Inhibitor Resorcylic Acid Lactone from Chaetomium chiversii

Shuhao Wang
, Yuquan Xu
, Erin A. Maine
, E. M.Kithsiri Wijeratne
, Patricia Espinosa-Artiles
, A. A.Leslie Gunatilaka
, István Molnár^*

^*Corresponding author for this work

Not published at VTT

University of Arizona

Research output: Contribution to journal › Article › Scientific › peer-review

112 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1328-1338
Journal	Chemistry and Biology
Volume	15
Issue number	12
DOIs	https://doi.org/10.1016/j.chembiol.2008.10.006
Publication status	Published - 22 Dec 2008
MoE publication type	A1 Journal article-refereed

Funding

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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CHEMBIO

Access to Document

10.1016/j.chembiol.2008.10.006

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title = "Functional Characterization of the Biosynthesis of Radicicol, an Hsp90 Inhibitor Resorcylic Acid Lactone from Chaetomium chiversii",

abstract = "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.",

keywords = "CHEMBIO",

author = "Shuhao Wang and Yuquan Xu and Maine, \{Erin A.\} and Wijeratne, \{E. M.Kithsiri\} and Patricia Espinosa-Artiles and Gunatilaka, \{A. A.Leslie\} and Istv{\'a}n Moln{\'a}r",

note = "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. ",

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doi = "10.1016/j.chembiol.2008.10.006",

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AU - Wang, Shuhao

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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

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DO - 10.1016/j.chembiol.2008.10.006

M3 - Article

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AN - SCOPUS:57649230837

SN - 1074-5521

VL - 15

SP - 1328

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JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 12

ER -

Functional Characterization of the Biosynthesis of Radicicol, an Hsp90 Inhibitor Resorcylic Acid Lactone from Chaetomium chiversii

Abstract

Funding

UN SDGs

Keywords

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