title: Molecular genetic analysis of the orsellinic acid/F9775 gene cluster of Aspergillus nidulans.
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.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, California 90089, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Sanchez
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Chiang
authors.forename: Edyta
authors.initials: E
authors.lastname: Szewczyk
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Davidson
authors.forename: Manmeet
authors.initials: M
authors.lastname: Ahuja
authors.forename: C
authors.initials: C
authors.lastname: Elizabeth Oakley
authors.forename: Jin
authors.initials: J
authors.lastname: Woo Bok
authors.forename: Nancy
authors.initials: N
authors.lastname: Keller
authors.forename: Berl R
authors.initials: BR
authors.lastname: Oakley
authors.forename: Clay C C
authors.initials: CC
authors.lastname: Wang
mesh_terms: D001233:Aspergillus nidulans / Q000201:enzymology / Q000235:genetics*; D001713:Biphenyl Compounds / Q000494:pharmacology; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D003512:Cyclohexanones / Q000378:metabolism; D004187:Disaccharides / Q000378:metabolism; D004987:Ethers / Q000494:pharmacology; D055786:Gene Knockout Techniques; D005810:Multigene Family; D048630:Polyketide Synthases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D012118:Resorcinols / Q000378:metabolism*
chemical_list: C477902:4-carboxy-5,5'-dihydroxy-3,3'-dimethyl-diphenylether; D001713:Biphenyl Compounds; D003470:Culture Media; D003512:Cyclohexanones; D004187:Disaccharides; D004987:Ethers; D047428:Protein Kinase Inhibitors; D012118:Resorcinols; C413265:tetraketide; C501612:orsellinic acid; D048630:Polyketide Synthases; D056657:Cathepsin K