Loading...
Biotechnological production optimization of argyrins - a potent immunomodulatory natural product class.
Pogorevc, Domen Müller, Rolf
Pogorevc, Domen
Müller, Rolf
Citations
Altmetric:
Advisors
Editors
Other Contributors
Issue Date
2021-11-01
Submitted date
Files
Loading...
Open Access publication
Adobe PDF, 871 KB
Other Titles
Abstract
Argyrins represent a family of cyclic octapeptides exhibiting promising immunomodulatory activity via inhibiting mitochondrial protein synthesis, which leads to reduced IL-17 production by the T-helper 17 cells. Argyrins are formed by a non-ribosomal peptide synthetase (NRPS), originating from the myxobacterial producer strains Archangium gephyra Ar8082 and Cystobacter sp. SBCb004. In this work, a previously established heterologous production platform was employed to provide evidence of direct D-configured amino acid incorporation by the argyrin assembly line. An adenylation domain of the argyrin NRPS was characterized and shown to have a high preference for D-configured amino acids. Eight novel argyrin derivatives were generated via biosynthetic engineering of the heterologous production system. The system was also optimized to enable formation of methylated argyrin C and D derivatives with improved immunosuppressive activity compared with their unmethylated counterparts. Furthermore, the optimization of cultivation conditions allowed exclusive production of one major derivative at a time, drastically improving the purification process. Importantly, engineering of transcription and translation initiation resulted in a substantially improved production titre reaching 350-400 mg l-1 . The optimized system presented herein thus provides a versatile platform for production of this promising class of immunosuppressants at a scale that should provide sufficient supply for upcoming pre-clinical development.
Citation
Microb Biotechnol. 2021 Nov 1. doi: 10.1111/1751-7915.13959. Epub ahead of print.
Publisher
Journal
PubMed ID
PubMed Central ID
Additional Links
Embedded video
Type
Article
Language
en
Description
Series/Report no.
ISSN
EISSN
1751-7915
ISBN
ISMN
Gov't Doc #
Sponsors
License
Attribution 4.0 International