Correlation of the avermectin polyketide synthase genes to the avermectin structure. Implications for designing novel avermectins.
Streptomyces avermitilis produces a series of eight potent anthelmintic compounds called avermectins (AVM). AVM are pentacyclic, macrocyclic lactone compounds containing an oleandrose disaccharide. Labeling studies have shown that AVM is a polyketide derived from the condensation of 12 acyl units (five propionates and seven acetates) to an isobutyl or 2-methylbutyryl starter unit. The genes required for AVM biosynthesis have been cloned, and deletion mapping has located the AVM gene cluster to a 95-kb region. Partial DNA sequencing of this region indicates two 30-kb segments encode large, multifunctional peptides of the AVM polyketide synthase (PKS). The PKS proteins contain at least 49 domains with homology to the domains in fatty acid synthase and erythromycin PKS. These domains are arranged as 12 modular repeats that each encode a PKS unit with various subsets of the FAS-like functions. The predicted functions required to form the side groups on the AVM macrocyclic ring were compared to the functions found in the 12 PKS units. This comparison suggests that each PKS unit is specific for condensation and reduction of one acyl unit. If the various domains can be manipulated without disrupting the PKS, it may be possible to synthesize a variety of AVM derivatives.
MacNeil
D J
DJ
Department of Microbial Chemotherapeutics and Molecular Genetics, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065.
Occi
J L
JL
Gewain
K M
KM
MacNeil
T
T
D000871:Anthelmintics / Q000737:chemistry / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000378:metabolism; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004917:Erythromycin / Q000378:metabolism; D005798:Genes, Bacterial; D005818:Genetic Engineering; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D018942:Macrolides; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism
D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D000981:Antiprotozoal Agents; D018942:Macrolides; D009097:Multienzyme Complexes; C056041:nemadectin; D004917:Erythromycin; D007559:Ivermectin; C019264:avermectin