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

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.

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch

References and Relationships

• Bibliographic citation: Divergent Tandem Acyl Carrier Proteins Necessitate In‐Series Polyketide Processing in the Leinamycin Family ; day:06 ; month:11 ; year:2024 ; extent:13 ; Angewandte Chemie / International edition. International edition ; (06.11.2024) (gesamt 13)

Contributors, Places and Time

• Creator: Phillips, Annabel P. ; Winter, Ashley J. ; Hooper, Chloe M. ; Williams, Christopher ; Crosby, John ; Willis, Christine L. ; Crump, Matthew P.

Further information

• DOI: 10.1002/anie.202414165
• URN: urn:nbn:de:101:1-2411061411151.463798750062
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:20 AM CEST