Biosynthesis, regulation, and engineering of a linear polyketide tautomycetin: a novel immunosuppressant in Streptomyces sp. CK4412

  • Si-Sun Choi
  • Hee-Ju Nah
  • Hye-rim Pyeon
  • Eung-Soo Kim
Natural Products - Review
  • 340 Downloads

Abstract

Tautomycetin (TMC) is a natural product with a linear structure that includes an ester bond connecting a dialkylmaleic moiety to a type I polyketide chain. Although TMC was originally identified as an antifungal antibiotic in the late 1980s, follow-up studies revealed its novel immunosuppressant activity. Specifically, TMC exhibited a mechanistically unique immunosuppressant activity about 100 times higher than that of cyclosporine A, a widely used immunosuppressant drug. Interestingly, a structurally close relative, tautomycin (TTM), was reported to not possess TMC-like immunosuppressant activity, suggesting that a distinctive polyketide moiety of TMC plays a critical role in immunosuppressant activity. Cloning and engineering of a TMC polyketide biosynthetic gene cluster generated several derivatives showing different biological activities. TMC was also found to be biosynthesized as a linear structure without forming a lactone ring, unlike the most polyketide-based compounds, implying the presence of a unique polyketide thioesterase in the cluster. Although TMC biosynthesis was limited due to its tight regulation by two pathway-specific regulatory genes located in the cluster, its production was significantly stimulated through homologous and heterologous expression of its entire biosynthetic gene cluster using a Streptomyces artificial chromosome vector system. In this mini-review, we summarize recent advances in the biosynthesis, regulation, and pathway engineering of a linear polyketide, TMC, in Streptomyces sp. CK4412.

Keywords

Tautomycetin Linear polyketide Biosynthesis Immunosuppressant 

Notes

Acknowledgments

This research was supported by the National Research Foundation of Korea (NRF-2014R1A2A1A11052236 and NRF-2015R1D1A4A01019447: S.-S. Choi), Ministry of Science, ICT and Future Planning (C1 Gas Refinery Program 2016M3D3A1A01913245), and Rural Development Administration (Cooperative Research Program for Agriculture Science and Technology Development PJ01129601).

Supplementary material

10295_2016_1847_MOESM1_ESM.docx (212 kb)
Supplementary material 1 (DOCX 211 kb)

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Copyright information

© Society for Industrial Microbiology and Biotechnology 2016

Authors and Affiliations

  • Si-Sun Choi
    • 1
  • Hee-Ju Nah
    • 1
  • Hye-rim Pyeon
    • 1
  • Eung-Soo Kim
    • 1
  1. 1.Department of Biological EngineeringInha UniversityIncheonKorea

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