Type III polyketide synthase beta-ketoacyl-ACP starter unit and ethylmalonyl-CoA extender unit selectivity discovered by Streptomyces coelicolor genome mining

J Am Chem Soc. 2006 Nov 22;128(46):14754-5. doi: 10.1021/ja065247w.


Polyketide synthases (PKSs) are involved in the biosynthesis of many important natural products. In bacteria, type III PKSs typically catalyze iterative decarboxylation and condensation reactions of malonyl-CoA building blocks in the biosynthesis of polyhydroxyaromatic products. Here it is shown that Gcs, a type III PKS encoded by the sco7221 ORF of the bacterium Streptomyces coelicolor, is required for biosynthesis of the germicidin family of 3,6-dialkyl-4-hydroxypyran-2-one natural products. Evidence consistent with Gcs-catalyzed elongation of specific beta-ketoacyl-ACP products of the fatty acid synthase FabH with ethyl- or methylmalonyl-CoA in the biosynthesis of germicidins is presented. Selectivity for beta-ketoacyl-ACP starter units and ethylmalonyl-CoA as an extender unit is unprecedented for type III PKSs, suggesting these enzymes may be capable of utilizing a far wider range of starter and extender units for natural product assembly than believed until now.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism*
  • Acyl Coenzyme A / metabolism*
  • Alcohol Oxidoreductases / metabolism*
  • Bacterial Proteins / metabolism*
  • Chromatography, High Pressure Liquid
  • Genome, Bacterial*
  • Isoenzymes / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Streptomyces coelicolor / genetics*


  • Acyl Coenzyme A
  • Bacterial Proteins
  • Isoenzymes
  • ethylmalonyl-coenzyme A
  • Alcohol Oxidoreductases
  • polyketide synthase ketoreductase
  • beta-ketoacyl-acyl carrier protein synthase I
  • 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase