Identification of the yeast ACC1 gene product (acetyl-CoA carboxylase) as the target of the polyketide fungicide soraphen A

Curr Genet. 1994 Feb;25(2):95-100. doi: 10.1007/BF00309532.

Abstract

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.

MeSH terms

  • Acetyl-CoA Carboxylase / antagonists & inhibitors*
  • Acetyl-CoA Carboxylase / genetics
  • Drug Resistance, Microbial
  • Fungal Proteins / antagonists & inhibitors*
  • Fungal Proteins / genetics
  • Fungicides, Industrial / pharmacology*
  • Heterocyclic Compounds / isolation & purification
  • Heterocyclic Compounds / pharmacology*
  • Macrolides*
  • Mutagenesis
  • Myxococcales / chemistry*
  • Saccharomyces cerevisiae / drug effects*
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics

Substances

  • Fungal Proteins
  • Fungicides, Industrial
  • Heterocyclic Compounds
  • Macrolides
  • soraphen A
  • Acetyl-CoA Carboxylase