Domain Organization and Active Site Architecture of a Polyketide Synthase C-methyltransferase

ACS Chem Biol. 2016 Dec 16;11(12):3319-3327. doi: 10.1021/acschembio.6b00759. Epub 2016 Oct 18.


Polyketide metabolites produced by modular type I polyketide synthases (PKS) acquire their chemical diversity through the variety of catalytic domains within modules of the pathway. Methyltransferases are among the least characterized of the catalytic domains common to PKS systems. We determined the domain boundaries and characterized the activity of a PKS C-methyltransferase (C-MT) from the curacin A biosynthetic pathway. The C-MT catalyzes S-adenosylmethionine-dependent methyl transfer to the α-position of β-ketoacyl substrates linked to acyl carrier protein (ACP) or a small-molecule analog but does not act on β-hydroxyacyl substrates or malonyl-ACP. Key catalytic residues conserved in both bacterial and fungal PKS C-MTs were identified in a 2 Å crystal structure and validated biochemically. Analysis of the structure and the sequences bordering the C-MT provides insight into the positioning of this domain within complete PKS modules.

Publication types

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

MeSH terms

  • Catalytic Domain
  • Crystallography, X-Ray
  • Cyanobacteria / chemistry
  • Cyanobacteria / enzymology*
  • Cyanobacteria / metabolism
  • Cyclopropanes / metabolism
  • Methyltransferases / chemistry*
  • Methyltransferases / metabolism
  • Models, Molecular
  • Polyketide Synthases / chemistry*
  • Polyketide Synthases / metabolism
  • Protein Conformation
  • Thiazoles / metabolism


  • Cyclopropanes
  • Thiazoles
  • curacin A
  • Polyketide Synthases
  • Methyltransferases