On-Line Polyketide Cyclization into Diverse Medium-Sized Lactones by a Specialized Ketosynthase Domain

Srividhya Sundaram, Hak Joong Kim, Ruth Bauer, Tawatchai Thongkongkaew, Daniel Heine, Christian Hertweck

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Ketosynthase (KS) domains of modular type I polyketide synthases (PKSs) typically catalyze the Claisen condensation of acyl and malonyl units to form linear chains. In stark contrast, the KS of the rhizoxin PKS branching module mediates a Michael addition, which sets the basis for a pharmacophoric δ-lactone moiety. The precise role of the KS was evaluated by site-directed mutagenesis, chemical probes, and biotransformations. Biochemical and kinetic analyses helped to dissect branching and lactonization reactions and unequivocally assign the entire sequence to the KS. Probing the range of accepted substrates with diverse synthetic surrogates in vitro, we found that the KS tolerates defined acyl chain lengths to produce five- to seven-membered lactones. These results show that the KS is multifunctional, as it catalyzes β-branching and lactonization. Information on the increased product portfolio of the unusual, TE-independent on-line cyclization is relevant for synthetic biology approaches.

Original languageEnglish
Pages (from-to)11223-11227
Number of pages5
JournalAngewandte Chemie - International Edition
Volume57
Issue number35
DOIs
Publication statusPublished - 2018 Aug 27
Externally publishedYes

Fingerprint

Polyketide Synthases
Polyketides
Mutagenesis
Cyclization
Lactones
Chain length
Condensation
Kinetics
Substrates
Synthetic Biology
Biotransformation
rhizoxin

Keywords

  • enzymes
  • lactones
  • macrolides
  • Michael addition
  • natural products

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

Cite this

On-Line Polyketide Cyclization into Diverse Medium-Sized Lactones by a Specialized Ketosynthase Domain. / Sundaram, Srividhya; Kim, Hak Joong; Bauer, Ruth; Thongkongkaew, Tawatchai; Heine, Daniel; Hertweck, Christian.

In: Angewandte Chemie - International Edition, Vol. 57, No. 35, 27.08.2018, p. 11223-11227.

Research output: Contribution to journalArticle

Sundaram, Srividhya ; Kim, Hak Joong ; Bauer, Ruth ; Thongkongkaew, Tawatchai ; Heine, Daniel ; Hertweck, Christian. / On-Line Polyketide Cyclization into Diverse Medium-Sized Lactones by a Specialized Ketosynthase Domain. In: Angewandte Chemie - International Edition. 2018 ; Vol. 57, No. 35. pp. 11223-11227.
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