title: Biosynthesis, regulation, and engineering of a linear polyketide tautomycetin: a novel immunosuppressant in Streptomyces sp. CK4412.
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.
authors.affiliation: Department of Biological Engineering, Inha University, Incheon, 402-751, Korea.
authors.forename: Si-Sun
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Department of Biological Engineering, Inha University, Incheon, 402-751, Korea.
authors.forename: Hee-Ju
authors.initials: HJ
authors.lastname: Nah
authors.affiliation: Department of Biological Engineering, Inha University, Incheon, 402-751, Korea.
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Pyeon
authors.affiliation: Department of Biological Engineering, Inha University, Incheon, 402-751, Korea. eungsoo@inha.ac.kr.
authors.forename: Eung-Soo
authors.initials: ES
authors.lastname: Kim
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D005663:Furans / Q000737:chemistry; D015964:Gene Expression Regulation, Bacterial; D005809:Genes, Regulator; D007166:Immunosuppressive Agents / Q000737:chemistry*; D008055:Lipids / Q000096:biosynthesis* / Q000737:chemistry; D000074041:Microorganisms, Genetically-Modified; D005810:Multigene Family; D061065:Polyketides / Q000737:chemistry; D015202:Protein Engineering; D013302:Streptomyces / Q000737:chemistry* / Q000235:genetics*
chemical_list: D000935:Antifungal Agents; D005663:Furans; D007166:Immunosuppressive Agents; D008055:Lipids; D061065:Polyketides; C058744:tautomycetin
keywords: Biosynthesis; Immunosuppressant; Linear polyketide; Tautomycetin