Diverse Combinatorial Biosynthesis Strategies for C-H Functionalization of Anthracyclinones

Rongbin Wang, Benjamin Nji Wandi, Nora Schwartz, Jacob Hecht, Larissa Ponomareva, Kendall Paige, Alexis West, Kathryn Desanti, Jennifer Nguyen, Jarmo Niemi, Jon S. Thorson, Khaled A. Shaaban, Mikko Metsä-Ketelä, S. Eric Nybo

Research output: Contribution to journalArticlepeer-review

Abstract

Streptomyces spp. are "nature's antibiotic factories" that produce valuable bioactive metabolites, such as the cytotoxic anthracycline polyketides. While the anthracyclines have hundreds of natural and chemically synthesized analogues, much of the chemical diversity stems from enzymatic modifications to the saccharide chains and, to a lesser extent, from alterations to the core scaffold. Previous work has resulted in the generation of a BioBricks synthetic biology toolbox in Streptomyces coelicolor M1152?matAB that could produce aklavinone, 9-epi-aklavinone, auramycinone, and nogalamycinone. In this work, we extended the platform to generate oxidatively modified analogues via two crucial strategies. (i) We swapped the ketoreductase and first-ring cyclase enzymes for the aromatase cyclase from the mithramycin biosynthetic pathway in our polyketide synthase (PKS) cassettes to generate 2-hydroxylated analogues. (ii) Next, we engineered several multioxygenase cassettes to catalyze 11-hydroxylation, 1-hydroxylation, 10-hydroxylation, 10-decarboxylation, and 4-hydroxyl regioisomerization. We also developed improved plasmid vectors and S. coelicolor M1152?matAB expression hosts to produce anthracyclinones. This work sets the stage for the combinatorial biosynthesis of bespoke anthracyclines using recombinant Streptomyces spp. hosts.

Original languageEnglish
Pages (from-to)1523-1536
Number of pages14
JournalACS Synthetic Biology
Volume13
Issue number5
DOIs
StatePublished - May 17 2024

Bibliographical note

Publisher Copyright:
© 2024 American Chemical Society. All rights reserved.

Keywords

  • BioBricks
  • Streptomyces coelicolor
  • anthracyclinones
  • anticancer
  • natural product biosynthesis
  • oxygenase
  • synthetic biology

ASJC Scopus subject areas

  • Biomedical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Fingerprint

Dive into the research topics of 'Diverse Combinatorial Biosynthesis Strategies for C-H Functionalization of Anthracyclinones'. Together they form a unique fingerprint.

Cite this