Structural and Functional Studies of the Daunorubicin Priming Ketosynthase DpsC

ACS Chem Biol. 2018 Jan 19;13(1):141-151. doi: 10.1021/acschembio.7b00551. Epub 2017 Dec 11.


Daunorubicin is a type II polyketide, one of a large class of polyaromatic natural products with anticancer, antibiotic, and antiviral activity. Type II polyketides are formed by the assembly of malonyl-CoA building blocks, though in rare cases, biosynthesis is initiated by the incorporation of a nonmalonyl derived starter unit, which adds molecular diversity to the poly-β-ketone backbone. Priming mechanisms for the transfer of novel starter units onto polyketide synthases (PKS) are still poorly understood. Daunorubicin biosynthesis incorporates a unique propionyl starter unit thought to be selected for by a subclass ("DpsC type") of priming ketosynthases (KS III). To date, however, no structural information exists for this subclass of KS III enzymes. Although selectivity for self-acylation with propionyl-CoA has previously been implied, we demonstrate that DpsC shows no discrimination for self-acylation or acyl-transfer to the cognate acyl carrier protein, DpsG with short acyl-CoAs. We present five crystal structures of DpsC, including apo-DpsC, acetyl-DpsC, propionyl-DpsC, butyryl-DpsC, and a cocrystal of DpsC with a nonhydrolyzable phosphopantetheine (PPant) analogue. The DpsC crystal structures reveal the architecture of the active site, the molecular determinants for catalytic activity and homology to O-malonyl transferases, but also indicate distinct differences. These results provide a structural basis for rational engineering of starter unit selection in type II polyketide synthases.

Publication types

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

MeSH terms

  • Acetyl Coenzyme A / chemistry
  • Acetyl Coenzyme A / metabolism
  • Acylation
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Catalytic Domain
  • Crystallography, X-Ray
  • Daunorubicin / metabolism*
  • Malonyl Coenzyme A / chemistry
  • Malonyl Coenzyme A / metabolism
  • Models, Molecular
  • Polyketide Synthases / chemistry*
  • Polyketide Synthases / genetics
  • Polyketide Synthases / metabolism*
  • Protein Conformation
  • Streptomyces / enzymology


  • Bacterial Proteins
  • Malonyl Coenzyme A
  • Acetyl Coenzyme A
  • Polyketide Synthases
  • Daunorubicin