Discovery and Heterologous Production of Tetrapetalones Provide Insights into the Formation of the Tetracyclic System.

Tetrapetalones make up a unique class of pentaketide ansamycins that feature a tetracyclic skeleton and exhibit potent inhibitory activities against soybean lipoxygenase. However, a detailed biosynthetic route to tetrapetalones has not been published. Herein we report the activation of the tetrapetalones' biosynthetic gene cluster (tpt) in Streptomyces sp. S10 by promoter engineering along with constitutive expression of pathway-specific regulator genes, leading to the discovery of seven new derivatives, tetrapetalones E-K (2-8), and the known tetrapetalone A (1). In vivo gene deletion experiments and heterologous expression of the minimized tpt cluster in Streptomyces albus J1074 suggest that the tetracyclic system of tetrapetalones is probably formed spontaneously, and the regioselective glycosylation of tetrapetalones at the C-9 hydroxy group with d-rhamnose or d-rhodinose was catalyzed by the glycosyltransferase Tpt14.

[1]  Yuemao Shen,et al.  Double Bond Geometric Isomers of Pentaketide Ansamycins from Streptomyces sp. S008. , 2023, Organic letters.

[2]  Dominic A. Colosimo,et al.  Nonenzymatic Reactions in Natural Product Formation. , 2022, Chemical reviews.

[3]  Y. Igarashi,et al.  Catellatolactams A-C, Plant Growth-Promoting Ansamacrolactams from a Rare Actinomycete of the Genus Catellatospora. , 2022, Journal of natural products.

[4]  Yuemao Shen,et al.  Targeted Discovery of Pentaketide Ansamycin Aminoansamycins A-G. , 2019, Organic letters.

[5]  Chunhua Lu,et al.  Pentaketide Ansamycin Microansamycins A-I from Micromonospora sp. Reveal Diverse Post-PKS Modifications. , 2018, Organic Letters.

[6]  T. Pettus,et al.  Synthetic Studies toward the Tetrapetalones: Diastereoselective Construction of a Putative Intermediate. , 2018, Organic Letters.

[7]  Jonas F. Buergler,et al.  Total Syntheses of (+)- and (-)-Tetrapetalones A and C. , 2017, Journal of the American Chemical Society.

[8]  J. L. Wood,et al.  Synthetic studies toward tetrapetalone A: attempted palladium π-allyl cascades toward a fused tricyclic intermediate , 2016 .

[9]  Peter N. Carlsen,et al.  Studies toward the AB ring system of the tetrapetalone natural products. , 2015, Tetrahedron.

[10]  Yuemao Shen,et al.  Activating a Cryptic Ansamycin Biosynthetic Gene Cluster To Produce Three New Naphthalenic Octaketide Ansamycins with n-Pentyl and n-Butyl Side Chains. , 2015, Organic letters.

[11]  Haoxin Wang,et al.  Identification of AstG1, A LAL Family Regulator that Positively Controls Ansatrienins Production in Streptomyces sp. XZQH13 , 2015, Current Microbiology.

[12]  A. Hoveyda,et al.  Synthesis of (±)-tetrapetalone A-Me aglycon. , 2014, Angewandte Chemie.

[13]  Yuemao Shen,et al.  Juanlimycins A and B, ansamycin macrodilactams from Streptomyces sp. , 2014, Organic letters.

[14]  Zhen Yang,et al.  Asymmetric total syntheses of ansamacrolactams (+)-Q-1047H-A-A and (+)-Q-1047H-R-A. , 2013, Organic letters.

[15]  Andrew P. Marcus,et al.  Synthesis of the tetracyclic core of tetrapetalone A enabled by a pyrrole reductive alkylation. , 2010, Organic Letters.

[16]  G. Bringmann,et al.  Cebulactams A1 and A2, new macrolactams isolated from Saccharopolyspora cebuensis, the first obligate marine strain of the genus Saccharopolyspora , 2008 .

[17]  A. Hirota,et al.  Ansaetherone, a New Radical Scavenger from Streptomyces sp. , 2008, Bioscience, biotechnology, and biochemistry.

[18]  Thomas F. Knight,et al.  Engineering BioBrick vectors from BioBrick parts , 2008, Journal of biological engineering.

[19]  V. Brecht,et al.  Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: The ethylmalonyl-CoA pathway , 2007, Proceedings of the National Academy of Sciences.

[20]  Y. Sugiyama,et al.  Biosynthesis of tetrapetalones. , 2007, Organic & biomolecular chemistry.

[21]  Kanyawim Kirtikara,et al.  Sulforhodamine B colorimetric assay for cytotoxicity screening , 2006, Nature Protocols.

[22]  T. Mahmud,et al.  Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699. , 2005, Microbiology.

[23]  J. Porco,et al.  Synthesis of the Tetracyclic Core of the Tetrapetalones through Transannular Oxidative [4+3] Cyclization , 2005 .

[24]  N. Abe,et al.  Novel Lipoxygenase Inhibitors, Tetrapetalone B, C, and D from Streptomyces sp. , 2004, Bioscience, biotechnology, and biochemistry.

[25]  H. Hirota,et al.  Revised structure of tetrapetalone A and its absolute stereochemistry , 2003 .

[26]  H. Hirota,et al.  Tetrapetalone A, a Novel Lipoxygense Inhibitor from Streptomyces sp. , 2003, Bioscience, biotechnology, and biochemistry.

[27]  R. M. Hann,et al.  The preparation of D-rhamnose from methyl alpha-d-mannopyranoside. , 1946, Journal of the American Chemical Society.

[28]  J. Porco,et al.  Synthesis of the tetracyclic core of the tetrapetalones through transannular oxidative [4+3] cyclization. , 2005, Angewandte Chemie.

[29]  K. Bock,et al.  A study of 13CH coupling constants in hexopyranoses , 1974 .