Ribosomal lipopeptides defined by distinct fatty N-acylation Florian Hubrich 1 , Nina M. Bösch 1 , Brandon I. Morinaka 2 , Michael Rust 1 , Muriel Gugger 3 , Serina L. Robinson 1,4 , Anna L. Vagstad 1 and Jörn Piel 1 1 ETH Zurich, Switzerland, 2 National University of Singapore, Singapore, 3 Institut Pasteur, France, 4 Eawag, Swiss Federal Institute of Aquatic Science and Technology, Switzerland Peptide natural products (NPs) provide valuable lead structures for drug discovery and drug development, as exemplified by the immunosuppressant cyclosporine or the lipopeptide and last resort antibiotic daptomycin. A longtime neglected superfamily of peptide NPs are the ribosomally-synthesized and post-translationally modified peptides (RiPPs). RiPPs are an extremely versatile class of NPs that is ubiquitous in all domains of life. 2 Among RiPPs, the proteusins – consisting of the pore-forming, cytotoxic polytheonamides and the bicyclic, antiviral landornamides – represent an outstanding diverse NP family. Although, only two subfamilies are characterized to date, they show structural diversity, a wealth of post-translational modifying (PTM) enzyme novelty and different bioactivity. 3–6 Recently, we discovered a novel proteusin subfamily that we termed selidamides using a targeted genome mining approach. 7 The characterized selidamide NPs, are ribosomal lipopeptides from different bacteria, the proteobacterium Pseudophaeobacterarcticus DSM23566 and the cyanobacteria Kamptomena sp. PCC6506 and Nostocpuntiforme PCC73102. These lipopeptides emphasize the predicted potential of the proteusin RiPP family regarding structural and enzymatic novelty. 8 Selidamides are defined by fatty N -acylation of diverse amino acid side-chains. 7 The fatty acids are likely from the primary metabolism lipid pool and require no additional biosynthetic pathway. Moreover, a novel family of the Gcn5-related N -acetyltransferase (GNAT) superfamily catalyze the distinct fatty acylation to the - N - or - N -position of (hydroxy)ornithine and lysine residue(s). We realized the structural elucidation of the selidamide NPs by combining a versatile set of methodology. Thereby, the final NPs revealed at least one (methyl)lanthionine ring as additional key structural feature. Such structural features ( N -acylation and macrocyclization) are typically known from non-ribosomal lipopeptides such as daptomycin or echinocandin. 1,9 Therefore, the PTM enzyme diversity of the proteusin RiPP family potentially provides a gene encoded route to biosynthesize (lipo)peptides mimicking peptide NPs from non-ribosomal origin. Finally, the side-chain fatty N -acylation with diverse substrates from primary metabolism represents a powerful tool for further biocatalytic improvement of peptide therapeutics. References 1. M. Muttenthaler, G. F. King, D. J. Adams, P. F. Alewood, Nat Rev Drug Discov , 2021, 20 , 309–325. 2. M. Montalbán-López, T et al. , Nat Prod Rep , 2020, 38 , 130–239. 3. M. F. Freeman, et al. , Science , 2012, 338 , 387–390. 4. M. F. Freeman, M. J. Helf, A. Bhushan, B. I. Morinaka and J. Piel, Nat Chem , 2017, 9 , 387–395. 5. N. M. Bösch, et al. , Angew Chem Int Ed , 2020, 59 , 11763–11768. 6. A. Bhushan, P. J. Egli, E. E. Peters, M. F. Freeman and J. Piel, Nat Chem , 2019, 11 , 931–939. 7. F. Hubrich et al., Proc Natl Acad Sci USA , 2022, 119 , e2113120119. 8. E. Dittmann, et al. , Int J Mol Sci , 2016, 17 , 1018. 9. W. Hüttel, Appl Microbiol Biotechnol , 2021, 105 , 55–66.
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