Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S-adenosyl-L-methionine

Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12295-300. doi: 10.1073/pnas.0901237106. Epub 2009 Jul 9.


Polyketides are among the major classes of bioactive natural products used to treat microbial infections, cancer, and other diseases. Here we describe a pathway to chloroethylmalonyl-CoA as a polyketide synthase building block in the biosynthesis of salinosporamide A, a marine microbial metabolite whose chlorine atom is crucial for potent proteasome inhibition and anticancer activity. S-adenosyl-L-methionine (SAM) is converted to 5'-chloro-5'-deoxyadenosine (5'-ClDA) in a reaction catalyzed by a SAM-dependent chlorinase as previously reported. By using a combination of gene deletions, biochemical analyses, and chemical complementation experiments with putative intermediates, we now provide evidence that 5'-ClDA is converted to chloroethylmalonyl-CoA in a 7-step route via the penultimate intermediate 4-chlorocrotonyl-CoA. Because halogenation often increases the bioactivity of drugs, the availability of a halogenated polyketide building block may be useful in molecular engineering approaches toward polyketide scaffolds.

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

  • Bacterial Proteins / classification
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Chromatography, High Pressure Liquid
  • Cladribine / chemistry
  • Cladribine / metabolism*
  • Cloning, Molecular
  • Gene Order
  • Genome, Bacterial / genetics
  • Kinetics
  • Lactones / chemistry
  • Lactones / metabolism*
  • Malonyl Coenzyme A / metabolism
  • Micromonosporaceae / genetics
  • Micromonosporaceae / metabolism
  • Models, Chemical
  • Molecular Sequence Data
  • Molecular Structure
  • Multigene Family
  • Mutation
  • Phylogeny
  • Polyketide Synthases / genetics
  • Polyketide Synthases / metabolism*
  • Pyrroles / chemistry
  • Pyrroles / metabolism*
  • S-Adenosylmethionine / metabolism*
  • Sequence Analysis, DNA
  • Substrate Specificity


  • Bacterial Proteins
  • Lactones
  • Pyrroles
  • Cladribine
  • Malonyl Coenzyme A
  • marizomib
  • Polyketide Synthases
  • S-Adenosylmethionine
  • 5'-chloro-5'-deoxyadenosine

Associated data

  • GENBANK/CP000667
  • GENBANK/EF397502