title: Transformations of cyclic nonaketides by Aspergillus terreus mutants blocked for lovastatin biosynthesis at the lovA and lovC genes.
abstract: Two mutants of Aspergillus terreus with either the lovC or lovA genes disrupted were examined for their ability to transform nonaketides into lovastatin 1, a cholesterol-lowering drug. The lovC disruptant was able to efficiently convert dihydromonacolin L 5 or monacolin J 9 into 1, and could also transform desmethylmonacolin J 15 into compactin 3. In contrast, the lovA mutant has an unexpectedly active beta-oxidation system and gives only small amounts of 1 upon addition of the immediate precursor 9, with most of the added nonaketide being degraded to heptaketide 22. Similarly, the lovA mutant does not accumulate the polyketide synthase product 5 and rapidly degrades any 5 added as a precursor via two cycles of beta-oxidation and hydroxylation at C-6 to give 20. The possible involvement of epoxides 21a and 21b in the biosynthesis of 1 was also examined, but their instability in fermentation media and fungal cells will require purified enzymes to establish their role.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
authors.forename: John L
authors.initials: JL
authors.lastname: Sorensen
authors.forename: Karine
authors.initials: K
authors.lastname: Auclair
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kennedy
authors.forename: C Richard
authors.initials: CR
authors.lastname: Hutchinson
authors.forename: John C
authors.initials: JC
authors.lastname: Vederas
mesh_terms: D001230:Aspergillus / Q000235:genetics*; D018360:Crystallography, X-Ray; D005285:Fermentation; D005656:Fungal Proteins / Q000235:genetics*; D008148:Lovastatin / Q000096:biosynthesis* / Q000737:chemistry*; D008956:Models, Chemical; D008957:Models, Genetic; D009097:Multienzyme Complexes / Q000235:genetics; D009154:Mutation; D009281:Naphthalenes / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism
chemical_list: C480100:4a,5-dihydromonacolin L5; D005656:Fungal Proteins; D009097:Multienzyme Complexes; D009281:Naphthalenes; C480099:lovA protein, Aspergillus terreus; C442940:lovC protein, Aspergillus terreus; D008148:Lovastatin; D010100:Oxygen