Dedicated ent-kaurene and ent-atiserene synthases for platensimycin and platencin biosynthesis

Michael J. Smanski, Zhiguo Yu, Jeffrey Casper, Shuangjun Lin, Ryan M. Peterson, Yihua Chen, Evelyn Wendt-Pienkowski, Scott R. Rajski, Ben Shen

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

Platensimycin (PTM) and platencin (PTN) are potent and selective inhibitors of bacterial and mammalian fatty acid synthases and have emerged as promising drug leads for both antibacterial and antidiabetic therapies. Comparative analysis of the PTM and PTN biosynthetic machineries in Streptomyces platensis MA7327 and MA7339 revealed that the divergence of PTM and PTN biosynthesis is controlled by dedicated ent-kaurene and ent-atiserene synthases, the latter of which represents a new pathway for diterpenoid biosynthesis. The PTM and PTN biosynthetic machineries provide a rare glimpse at how secondary metabolic pathway evolution increases natural product structural diversity and support the wisdom of applying combinatorial biosynthesis methods for the generation of novel PTM and/or PTN analogues, thereby facilitating drug development efforts based on these privileged natural product scaffolds.

Original languageEnglish (US)
Pages (from-to)13498-13503
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number33
DOIs
StatePublished - Aug 16 2011

Keywords

  • Antibiotic
  • Biosynthetic gene cluster
  • Metabolic pathway engineering
  • Terpene synthase
  • ent-copalyl diphosphate

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