Molecular genetic analysis of the orsellinic acid/F9775 gene cluster of Aspergillus nidulans

James F. Sanchez; Yi-Ming Chiang; Edyta Szewczyk; Ashley D. Davidson; Manmeet Ahuja; C. Elizabeth Oakley; Jin Woo Bok; Nancy Keller; Berl R. Oakley; Clay C. C. Wang

doi:10.1039/B904541D

Molecular genetic analysis of the orsellinic acid/F9775 genecluster of Aspergillus nidulans†‡

James F. Sanchez,^a Yi-Ming Chiang,^ac Edyta Szewczyk,§^d Ashley D. Davidson,^d Manmeet Ahuja,^g C. Elizabeth Oakley,^dg Jin Woo Bok,^ef Nancy Keller,^ef Berl R. Oakley^dg and Clay C. C. Wang*^ab

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^a Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, California 90089, USA
E-mail: clayw@usc.edu
Fax: +1 323 442 1390
Tel: +1 323 442 1670

^b Department of Chemistry, University of Southern California, College of Letters, Arts, and Sciences, Los Angeles, California 90089, USA

^c Graduate Institute of Pharmaceutical Science, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan

^d Department of Molecular Genetics, Ohio State University, 484 West 12th Avenue, Columbus, Ohio 43210, USA

^e Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA

^f Department of Bacteriology, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA

^g Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave., Lawrence

Abstract

F-9775A and F-9775B are cathepsin K inhibitors that arise from a chromatin remodelling deletant strain of Aspergillus nidulans. A polyketide synthase gene has been determined to be responsible for their formation and for the simpler, archetypical polyketide orsellinic acid. We have discovered simple culture conditions that result in the production of the three compounds, and this facilitates analysis of the genes responsible for their synthesis. We have now analysed the F9775/orsellinic acid gene cluster using a set of targeted deletions. We find that the polyketide synthase alone is required for orsellinic acid biosynthesis and only two additional genes in the cluster are required for F9775 A and B synthesis. Our deletions also yielded the bioactive metabolites gerfelin and diorcinol.

Molecular BioSystems

Molecular genetic analysis of the orsellinic acid/F9775 genecluster of Aspergillus nidulans†‡

Abstract

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Molecular genetic analysis of the orsellinic acid/F9775 gene cluster of Aspergillus nidulans

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