Widespread microbial utilization of ribosomal β-amino acid-containing peptides and proteins
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Date
2022-10-13
Publication Type
Journal Article
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yes
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Abstract
β-Amino residues are regarded as extremely rare features among ribosomal products. They can be installed by a remarkable non-canonical enzymatic splicing process occurring in some Nif11-type ribosomally synthesized and posttranslationally modified peptide (RiPP) pathways from select cyanobacteria. The functions of the final pathway products remained unknown. Here, a global bioinformatic analysis suggested an unexpectedly broad distribution of ribosomal β-amino acid products in diverse bacterial lineages as well as archaea. Characterization of 27 bacterial splicease-substrate pairs confirmed the modification in all cases. The “spliceotide” products include many previously unrecognized RiPP types as well as proteins, contain 35 to >600 residues, and feature single to multiple α-keto-β-amino acid moieties, with 15 different naturally occurring β units characterized and 20 predicted. Of three tested spliceotides, all exhibited exceptionally potent protease inhibitory activity, providing a potential rationale for the widespread splicease chemistry in prokaryotes and highlighting substantial potential for drug discovery and gene-based biomolecule diversification.
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published
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Journal / series
Volume
8 (10)
Pages / Article No.
2659 - 2677
Publisher
Elsevier
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Edition / version
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Date collected
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Subject
natural products; peptides; proteins; β-amino acids; bacteria; protease inhibitors; genome mining; ribosomally synthesized and posttranslationally modified peptides; ketoamides
Organisational unit
03861 - Bode, Jeffrey W. / Bode, Jeffrey W.
03980 - Piel, Jörn / Piel, Jörn
Notes
Funding
897571 - Functional Exploration of Biosynthetic Dark Matter in the Human Gut Microbiome (EC)
20-1 FEL-07 - Metagenome mining to investigate the function, mobility, and evolution of biosynthetic pathways in the global ocean (ETHZ)
742739 - Tailored chemical complexity through evolution-inspired synthetic biology (EC)
185077 - Investigating and utilizing uncultivated bacteria as a rich resource of bioactive natural products (SNF)
167051 - Ecosystem- and genome-guided antibiotic discovery (SNF)
ETH-21 21-2 - A single-cell bacterial synthetic biology platform for the biosynthesis and screening of protease-inhibitory peptide drug leads (ETHZ)
169451 - Protein Synthesis with Chemoselective Ligations (SNF)
20-1 FEL-07 - Metagenome mining to investigate the function, mobility, and evolution of biosynthetic pathways in the global ocean (ETHZ)
742739 - Tailored chemical complexity through evolution-inspired synthetic biology (EC)
185077 - Investigating and utilizing uncultivated bacteria as a rich resource of bioactive natural products (SNF)
167051 - Ecosystem- and genome-guided antibiotic discovery (SNF)
ETH-21 21-2 - A single-cell bacterial synthetic biology platform for the biosynthesis and screening of protease-inhibitory peptide drug leads (ETHZ)
169451 - Protein Synthesis with Chemoselective Ligations (SNF)