Expanded ribosomal synthesis of non-standard cyclic backbones in vitro
Abstract The ribosome polymerizes L-α-amino acids into polypeptides, catalyzing peptide bond formation through aminolysis. This process is facilitated by entropy trapping within its peptidyl transferase center (PTC). In this research, we harness this capability to synthesize polymers containing cycl...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60126-4 |
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| author | Kanghun Lee Hyeongwoo Park Ravi Kumar Devarapalli Dahye Im Jongcheol Seo Joongoo Lee |
| author_facet | Kanghun Lee Hyeongwoo Park Ravi Kumar Devarapalli Dahye Im Jongcheol Seo Joongoo Lee |
| author_sort | Kanghun Lee |
| collection | DOAJ |
| description | Abstract The ribosome polymerizes L-α-amino acids into polypeptides, catalyzing peptide bond formation through aminolysis. This process is facilitated by entropy trapping within its peptidyl transferase center (PTC). In this research, we harness this capability to synthesize polymers containing cyclic motifs in the backbone. We design 26 non-canonical monomers (ncMs) with two distinct substrates: dicarboxylic esters and hydrazinoesters, each containing bifunctional moieties that undergo ring-closing reactions through multiple aminolysis reactions. Using a cell-free system that enables the consecutive incorporation of these ncMs into a growing peptide, we discover that the ribosome can produce 5- and 6-membered cyclic backbones, which have never been reported. We also demonstrate that the formation of such cyclic backbones within the ribosome is tunable by altering the substituents of dicarboxylic esters. This discovery expands the range of non-standard backbones that can be synthesized by the ribosome and motivates future research towards expanding ribosome-mediated chemistries for biopolymer synthesis. |
| format | Article |
| id | doaj-art-483615c096ff405ebb7fc351a668bc1b |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-483615c096ff405ebb7fc351a668bc1b2025-08-20T02:03:31ZengNature PortfolioNature Communications2041-17232025-05-0116111410.1038/s41467-025-60126-4Expanded ribosomal synthesis of non-standard cyclic backbones in vitroKanghun Lee0Hyeongwoo Park1Ravi Kumar Devarapalli2Dahye Im3Jongcheol Seo4Joongoo Lee5Division of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology (POSTECH)Division of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology (POSTECH)Department of Chemical Engineering, Pohang University of Science and Technology (POSTECH)Department of Chemistry, Pohang University of Science and Technology (POSTECH)Division of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology (POSTECH)Division of Interdisciplinary Bioscience and Bioengineering (I-Bio), Pohang University of Science and Technology (POSTECH)Abstract The ribosome polymerizes L-α-amino acids into polypeptides, catalyzing peptide bond formation through aminolysis. This process is facilitated by entropy trapping within its peptidyl transferase center (PTC). In this research, we harness this capability to synthesize polymers containing cyclic motifs in the backbone. We design 26 non-canonical monomers (ncMs) with two distinct substrates: dicarboxylic esters and hydrazinoesters, each containing bifunctional moieties that undergo ring-closing reactions through multiple aminolysis reactions. Using a cell-free system that enables the consecutive incorporation of these ncMs into a growing peptide, we discover that the ribosome can produce 5- and 6-membered cyclic backbones, which have never been reported. We also demonstrate that the formation of such cyclic backbones within the ribosome is tunable by altering the substituents of dicarboxylic esters. This discovery expands the range of non-standard backbones that can be synthesized by the ribosome and motivates future research towards expanding ribosome-mediated chemistries for biopolymer synthesis.https://doi.org/10.1038/s41467-025-60126-4 |
| spellingShingle | Kanghun Lee Hyeongwoo Park Ravi Kumar Devarapalli Dahye Im Jongcheol Seo Joongoo Lee Expanded ribosomal synthesis of non-standard cyclic backbones in vitro Nature Communications |
| title | Expanded ribosomal synthesis of non-standard cyclic backbones in vitro |
| title_full | Expanded ribosomal synthesis of non-standard cyclic backbones in vitro |
| title_fullStr | Expanded ribosomal synthesis of non-standard cyclic backbones in vitro |
| title_full_unstemmed | Expanded ribosomal synthesis of non-standard cyclic backbones in vitro |
| title_short | Expanded ribosomal synthesis of non-standard cyclic backbones in vitro |
| title_sort | expanded ribosomal synthesis of non standard cyclic backbones in vitro |
| url | https://doi.org/10.1038/s41467-025-60126-4 |
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