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Combinatorial biosynthesis yields novel hybrid argimycin P alkaloids with diverse scaffolds in Streptomyces argillaceus |
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| Authors: | Suhui Ye Giovanni Ballin Ignacio Pérez-Victoria Alfredo F. Braña Jesús Martín Fernando Reyes José A. Salas Carmen Méndez |
| Affiliation: | 1. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria de Asturias (ISPA), Oviedo, Spain Contribution: Conceptualization (equal), Investigation (equal), Writing - original draft (equal);2. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Oviedo, Spain Contribution: Investigation (equal);3. Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Armilla, Granada, Spain Contribution: Investigation (equal);4. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Oviedo, Spain Contribution: Investigation (supporting);5. Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Armilla, Granada, Spain Contribution: Investigation (supporting);6. Fundación MEDINA, Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Armilla, Granada, Spain;7. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Oviedo, Spain Instituto de Investigación Sanitaria de Asturias (ISPA), Oviedo, Spain Contribution: Conceptualization (equal), Funding acquisition (equal);8. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo, Oviedo, Spain |
| Abstract: | Coelimycin P1 and argimycins P are two types of polyketide alkaloids produced by Streptomyces coelicolor and Streptomyces argillaceus, respectively. Their biosynthesis pathways share some early steps that render very similar aminated polyketide chains, diverging the pathways afterwards. By expressing the putative isomerase cpkE and/or the putative epoxidase/dehydrogenase cpkD from the coelimycin P1 gene cluster into S. argillaceus wild type and in argimycin mutant strains, five novel hybrid argimycins were generated. Chemical characterization of those compounds revealed that four of them show unprecedented scaffolds (quinolizidine and pyranopyridine) never found before in the argimycin family of compounds. One of these compounds (argimycin DM104) shows improved antibiotic activity. Noticeable, biosynthesis of these quinolizidine argimycins results from a hybrid pathway created by combining enzymes from two different pathways, which utilizes an aminated polyketide chain as precursor instead of lysine as it occurs for other quinolizidines. |
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