Divergent Tandem Acyl Carrier Proteins Necessitate In-Series Polyketide Processing in the Leinamycin Family

Annabel P Phillips, Ashley J Winter, Chloe Hooper, Christopher Williams, John Crosby, Chris L Willis*, Matthew P Crump*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The leinamycin family of polyketides are promising antitumor antibiotics, yet several aspects of their biosynthesis remain elusive. All leinamycin family members bear a sulfur-containing moiety which is essential for the anticancer activity exhibited by leinamycin. The key building blocks required for the incorporation of these functionalities are introduced in the final module of the polyketide synthase (PKS), which elegantly combines β-branching and thiocysteine incorporation to generate a diverse library of sulfur-based molecular scaffolds. Two acyl carrier proteins (ACPs) form a key didomain component of this module, but their amino acid sequence divergence has brought into question the common notion of functional equivalence. Here, we provide unprecedented functional evidence that these tandem ACPs play distinct roles in the final module of polyketide assembly. Using the weishanmycin biosynthetic pathway as a template, the in vitro reconstitution of key polyketide chain extension and β-branching steps in this module has revealed strict functional selectivity for a single ACP. Furthermore, we propose a cryptic transacylation step must occur prior to polyketide off-loading and cyclization. Altogether, these mechanistic investigations suggest that an atypical in-series mechanism underpins sulfur incorporation in the leinamycin family, and provides significant progress towards delineating their late-stage assembly.
Original languageEnglish
Article numbere202414165
Number of pages12
JournalAngewandte Chemie
Volume137
Issue number2
Early online date26 Sept 2024
DOIs
Publication statusPublished - 10 Jan 2025

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Angewandte Chemie published by Wiley-VCH GmbH.

Research Groups and Themes

  • Bristol BioDesign Institute
  • BrisSynBio

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