Identification of the yeast ACC1 gene product (acetyl-CoA carboxylase) as the target of the polyketide fungicide soraphen A.
Soraphen A, a polyketide isolated from the myxobacterium Sorangium cellulosum, is a potent inhibitor of fungal growth. We have used a genetic approach to localize the target of this drug, employing Saccharomyces cerevisiae as a model organism. we have isolated soraphen A-resistant mutants and found that all of them map at the same genetic locus and exhibit a broad range of semidominant phenotypes. Data from genetic crosses of soraphen A-resistant clones with an acc1 mutant revealed that ACC1, coding for acetyl-CoA carboxylase (E.C. 6.4.1.2), is tightly linked to soraphen A resistance. Partially-purified enzyme extracts containing acetyl-CoA carboxylase were prepared and assayed for their soraphen A sensitivity. Our experiments showed that the catalytic activity of the wild-type enzyme is inhibited in vitro by soraphen A while the mutant enzyme remains catalytically active. Taken together these data strongly suggest that the ACC1 gene product is the primary target for soraphen A in vivo.
Vahlensieck
H F
HF
Ciba-Geigy AG, Biotechnology Department K-681.109, Basel, Switzerland.
Pridzun
L
L
Reichenbach
H
H
Hinnen
A
A
D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D004352:Drug Resistance, Microbial; D005656:Fungal Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D005659:Fungicides, Industrial / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000302:isolation & purification / Q000494:pharmacology*; D018942:Macrolides; D016296:Mutagenesis; D009231:Myxococcales / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics
D005656:Fungal Proteins; D005659:Fungicides, Industrial; D006571:Heterocyclic Compounds; D018942:Macrolides; C086151:soraphen A; D000103:Acetyl-CoA Carboxylase