Biosynthesis, regulation, and engineering of a linear polyketide tautomycetin: a novel immunosuppressant in Streptomyces sp. CK4412. (1st May 2017)

• Record Type: Journal Article
• Authors: Choi, Si-Sun; Nah, Hee-Ju; Pyeon, Hye-rim; Kim, Eung-Soo
• Is Part Of: Journal of industrial microbiology & biotechnology. Volume 44:Number 4/5(2017)
• Page Start: 555
• Page End: 561
• Publication Date: 2017-05-01
• Subjects: Tautomycetin -- Linear polyketide -- Biosynthesis -- Immunosuppressant; Industrial microbiology -- Periodicals; 660.62
• DOI: 10.1007/s10295-016-1847-2
• Languages: English
• ISSNs: 1367-5435

Abstract

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.