Biosynthesis, regulation, and engineering of a linear polyketide tautomycetin: a novel immunosuppressant in Streptomyces sp. CK4412
- 340 Downloads
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.
KeywordsTautomycetin Linear polyketide Biosynthesis Immunosuppressant
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).
- 34.Park SH, Choi SS, Sherman DH, Kim ES (2009) A global positive regulator afsR2 stimulates tautomycetin production via pathway-specific regulatory gene over-expression in Streptomyces sp. CK4412. Proc. Biochem 44(11):1298–1301Google Scholar
- 36.Scaglione JB, Akey DL, Sullivan R, Kittendorf JD, Rath CM, Kim ES, Smith JL, Sherman DH (2010) Biochemical and structural characterization of the tautomycetin thioesterase: analysis of a stereoselective polyketide hydrolase. Angew Chem Int Ed Engl 49(33):5726–5730CrossRefPubMedPubMedCentralGoogle Scholar