Transformations of cyclic nonaketides by Aspergillus terreus mutants blocked for lovastatin biosynthesis at the lovA and lovC genes.
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.
Sorensen
John L
JL
Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
Auclair
Karine
K
Kennedy
Jonathan
J
Hutchinson
C Richard
CR
Vederas
John C
JC
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
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