New Prodigiosin Derivatives Obtained by Mutasynthesis in Pseudomonas putida
| Autor: | Luca Laraia, Anita Loeschcke, Karl-Erich Jaeger, Sonja Sievers, Hannah U. C. Brass, Andreas Sebastian Klein, Andreas Domröse, Joerg Pietruszka, Thomas Classen, Patrick Bongen, Thomas Drepper |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Biomedical Engineering Human pathogen 01 natural sciences Biochemistry Genetics and Molecular Biology (miscellaneous) Microbiology Metabolic engineering Prodigiosin 03 medical and health sciences chemistry.chemical_compound Genes Synthetic biology Pseudomonas putida 010405 organic chemistry Streptomycetaceae General Medicine Antimicrobial biology.organism_classification Anti-Bacterial Agents Up-Regulation 0104 chemical sciences Genetic Enhancement 030104 developmental biology Metabolic Engineering Biochemistry chemistry Mutation Serratia marcescens Bacteria |
| Zdroj: | ACS Synthetic Biology. 6:1757-1765 |
| ISSN: | 2161-5063 |
| Popis: | The deeply red-colored natural compound prodigiosin is a representative of the prodiginine alkaloid family, which possesses bioactivities as antimicrobial, antitumor, and antimalarial agents. Various bacteria including the opportunistic human pathogen Serratia marcescens and different members of the Streptomycetaceae and Pseudoalteromonadaceae produce prodiginines. In addition, these microbes generally accumulate many structurally related alkaloids making efficient prodiginine synthesis and purification difficult and expensive. Furthermore, it is known that structurally different natural prodiginine variants display differential bioactivities. In the herein described mutasynthesis approach, 13 different derivatives of prodigiosin were obtained utilizing the GRAS (generally recognized as safe) classified strain Pseudomonas putida KT2440. Genetic engineering of the prodigiosin pathway together with incorporation of synthetic intermediates thus resulted in the formation of a so far unprecedented structural diversity of new prodiginine derivatives in P. putida. Furthermore, the formed products allow reliable conclusions regarding the substrate specificity of PigC, the final condensing enzyme in the prodigiosin biosynthesis pathway of S. marcescens. The biological activity of prodigiosin toward modulation of autophagy was preserved in prodiginine derivatives. One prodiginine derivative displayed more potent autophagy inhibitory activity than the parent compound or the synthetic clinical candidate obatoclax. |
| Databáze: | OpenAIRE |
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