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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...

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Autores principales: Walker, Joshua A., Hamlish, Noah, Tytla, Avery, Brauer, Daniel D., Francis, Matthew B., Schepartz, Alanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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