Back to Search
Start Over
Overexpression of a type III PKS gene affording novel violapyrones with enhanced anti-influenza A virus activity.
- Source :
-
Microbial Cell Factories . 4/12/2018, Vol. 17 Issue 1, pN.PAG-N.PAG. 1p. 3 Diagrams, 3 Charts, 3 Graphs. - Publication Year :
- 2018
-
Abstract
- Background: Type III polyketide synthases (PKSs) are simple homodimer ketosynthases that distribute across plants, fungi, and bacteria, catalyzing formation of pyrone- and resorcinol-types aromatic polyketides with various bioactivities. The broad substrate promiscuity displayed by type III PKSs makes them wonderful candidates for expanding chemical diversity of polyketides. Results: Violapyrone B (VLP B, <bold>10</bold>), an α-pyrone compound produced by deepsea-derived <italic>Streptomyces somaliensis</italic> SCSIO ZH66, is encoded by a type III PKS VioA. We overexpressed VioA in three different hosts, including <italic>Streptomyces coelicolor</italic> M1146, <italic>Streptomyces sanyensis</italic> FMA as well as the native producer <italic>S. somaliensis</italic> SCSIO ZH66, leading to accumulation of different violapyrone compounds. Among them, <italic>S. coelicolor</italic> M1146 served as the host producing the most abundant violapyrones, from which five new (<bold>2</bold>–<bold>4</bold>, <bold>7</bold> and <bold>12</bold>) and nine known (<bold>1</bold>, <bold>5</bold>, <bold>6</bold>, <bold>8</bold>–<bold>11</bold>, <bold>13</bold> and <bold>14</bold>) compounds were identified. Anti-influenza A (H1N1) virus activity of these compounds was then evaluated using ribavirin as a positive control (IC50 = 112.9 μM), revealing that compounds <bold>11</bold>–<bold>14</bold> showed considerable activity with IC50 values of 112.7, 26.9, 106.7 and 28.8 μM, respectively, which are significantly improved as compared to that of VLP B (<bold>10</bold>) (IC50 > 200 μM). The productions of <bold>10</bold> and <bold>13</bold> were increased by adding P450 inhibitor metyrapone. In addition, site-directed mutagenesis experiment led to demonstration of the residue S242 to be essential for the activity of VioA. Conclusions: Biological background of the expression hosts is an important factor impacting on the encoding products of type III PKSs. By using <italic>S. coelicolor</italic> M1146 as cell factory, we were able to generate fourteen VLPs compounds. Anti-H1N1 activity assay suggested that the lipophilic nature of the alkyl chains of VLPs plays an important role for the activity, providing valuable guidance for further structural optimization of VLPs. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 14752859
- Volume :
- 17
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Microbial Cell Factories
- Publication Type :
- Academic Journal
- Accession number :
- 129028007
- Full Text :
- https://doi.org/10.1186/s12934-018-0908-9