Abstract
The strain Streptomyces cacaoi CA-170360 produces the cyclic pentapeptides pentaminomycins A–H and BE-18257 A–C, two families of cyclopeptides synthesized by two non-ribosomal peptide synthetases encoded in tandem within the same biosynthetic gene cluster. In this work, we have cloned and confirmed the heterologous expression of this biosynthetic gene cluster, demonstrating that each of the non-ribosomal peptide synthetases present in the cluster is involved in the biosynthesis of each group of cyclopeptides. In addition, we discuss the involvement of a stand-alone enzyme belonging to the Penicillin Binding Protein family in the release and macrocyclization of the peptides.
Highlights
Cyclic peptides are one of the most important chemical classes of biomolecules with potential therapeutic applications
The productions of pentaminomycins in the heterologous host S. albus/pCPP2 were still at the limit of detection from most of the compounds. These results clearly demonstrate that the first non-ribosomal peptide synthetases (NRPS) gene is responsible for the biosynthesis of BE-18257 antibiotics, and that the second NRPS gene synthesizes pentaminomycins
We have shown that BE-18257 antibiotics and pentaminomycins can be produced
Summary
Cyclic peptides are one of the most important chemical classes of biomolecules with potential therapeutic applications. The cyclic polypeptide chain is formed by amide bonds between proteinogenic or nonproteinogenic amino acids, with a structure that confers reduced conformational flexibility, resistance to exo- and endo-peptidases, increased cell permeability and better biological activities compared with their linear counterparts. These molecules show, in general, low toxicity, good binding affinity and target selectivity [1,2]. Bacterial cyclic peptides exhibit a wide variety of biological activities. New bacterial bioactive cyclopeptides have been reported, such as pargamicins A–D [6,7], cyclotetrapeptides cyclo-(Leu-Pro-Ile-Pro) and cyclo-(Tyr-Pro-Phe-Gly) [8], the cyclic pentapeptides BE-18257
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