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Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates
[Image: see text] Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products with potent antibiotic, antiviral, and anticancer properties. RiPP enzymes known as cyclodehydratases and dehydrogenases work together to catalyze intramolecular, inter-r...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052802/ https://www.ncbi.nlm.nih.gov/pubmed/35505866 http://dx.doi.org/10.1021/acscentsci.1c01577 |
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author | Walker, Joshua A. Hamlish, Noah Tytla, Avery Brauer, Daniel D. Francis, Matthew B. Schepartz, Alanna |
author_facet | Walker, Joshua A. Hamlish, Noah Tytla, Avery Brauer, Daniel D. Francis, Matthew B. Schepartz, Alanna |
author_sort | Walker, Joshua A. |
collection | PubMed |
description | [Image: see text] Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products with potent antibiotic, antiviral, and anticancer properties. RiPP enzymes known as cyclodehydratases and dehydrogenases work together to catalyze intramolecular, inter-residue condensation and dehydrogenation reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here, we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers—including aminobenzoic acid derivatives and beta-amino acids—within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse non-α-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond—both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code. |
format | Online Article Text |
id | pubmed-9052802 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-90528022022-05-02 Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates Walker, Joshua A. Hamlish, Noah Tytla, Avery Brauer, Daniel D. Francis, Matthew B. Schepartz, Alanna ACS Cent Sci [Image: see text] Ribosomally synthesized and post-translationally modified peptides (RiPPs) are peptide-derived natural products with potent antibiotic, antiviral, and anticancer properties. RiPP enzymes known as cyclodehydratases and dehydrogenases work together to catalyze intramolecular, inter-residue condensation and dehydrogenation reactions that install oxazoline/oxazole and thiazoline/thiazole heterocycles within ribosomally produced polypeptide chains. Here, we show that the previously reported enzymes MicD-F and ArtGox accept backbone-modified monomers—including aminobenzoic acid derivatives and beta-amino acids—within leader-free polypeptides, even at positions immediately preceding or following the site of cyclization/dehydrogenation. The products are sequence-defined chemical polymers with multiple, diverse non-α-amino acid subunits. We show further that MicD-F and ArtGox can install heterocyclic backbones within protein loops and linkers without disrupting the native tertiary fold. Calculations reveal the extent to which these heterocycles restrict conformational space; they also eliminate a peptide bond—both features could improve the stability or add function to linker sequences now commonplace in emerging biotherapeutics. This work represents a general strategy to expand the chemical diversity of the proteome beyond and in synergy with what can now be accomplished by expanding the genetic code. American Chemical Society 2022-03-21 2022-04-27 /pmc/articles/PMC9052802/ /pubmed/35505866 http://dx.doi.org/10.1021/acscentsci.1c01577 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Walker, Joshua A. Hamlish, Noah Tytla, Avery Brauer, Daniel D. Francis, Matthew B. Schepartz, Alanna Redirecting RiPP Biosynthetic Enzymes to Proteins and Backbone-Modified Substrates |
title | Redirecting RiPP Biosynthetic Enzymes to Proteins
and Backbone-Modified Substrates |
title_full | Redirecting RiPP Biosynthetic Enzymes to Proteins
and Backbone-Modified Substrates |
title_fullStr | Redirecting RiPP Biosynthetic Enzymes to Proteins
and Backbone-Modified Substrates |
title_full_unstemmed | Redirecting RiPP Biosynthetic Enzymes to Proteins
and Backbone-Modified Substrates |
title_short | Redirecting RiPP Biosynthetic Enzymes to Proteins
and Backbone-Modified Substrates |
title_sort | redirecting ripp biosynthetic enzymes to proteins
and backbone-modified substrates |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9052802/ https://www.ncbi.nlm.nih.gov/pubmed/35505866 http://dx.doi.org/10.1021/acscentsci.1c01577 |
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