Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, Pamtides
Abstract Ribosomally synthesized and post‐translationally modified peptides (RiPPs) are a structurally diverse class of natural products with a distinct biosynthetic logic, the enzymatic modification of genetically encoded precursor peptides. Although their structural and biosynthetic diversity rema...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202305946 |
| _version_ | 1797356407267262464 |
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| author | Hyunbin Lee Sho Hee Park Jiyoon Kim Jaehak Lee Min Sun Koh Jung Ho Lee Seokhee Kim |
| author_facet | Hyunbin Lee Sho Hee Park Jiyoon Kim Jaehak Lee Min Sun Koh Jung Ho Lee Seokhee Kim |
| author_sort | Hyunbin Lee |
| collection | DOAJ |
| description | Abstract Ribosomally synthesized and post‐translationally modified peptides (RiPPs) are a structurally diverse class of natural products with a distinct biosynthetic logic, the enzymatic modification of genetically encoded precursor peptides. Although their structural and biosynthetic diversity remains largely underexplored, the identification of novel subclasses with unique structural motifs and biosynthetic pathways is challenging. Here, it is reported that peptide/protein L‐aspartyl O‐methyltransferases (PAMTs) present in several RiPP subclasses are highly homologous. Importantly, it is discovered that the apparent evolutionary transmission of the PAMT gene to unrelated RiPP subclasses can serve as a basis to identify a novel RiPP subclass. Biochemical and structural analyses suggest that homologous PAMTs convert aspartate to isoaspartate via aspartyl‐O‐methyl ester and aspartimide intermediates, and often require cyclic or hairpin‐like structures for modification. By conducting homology‐based bioinformatic analysis of PAMTs, over 2,800 biosynthetic gene clusters (BGCs) are identified for known RiPP subclasses in which PAMTs install a secondary modification, and over 1,500 BGCs where PAMTs function as a primary modification enzyme, thereby defining a new RiPP subclass, named pamtides. The results suggest that the genome mining of proteins with secondary biosynthetic roles can be an effective strategy for discovering novel biosynthetic pathways of RiPPs through the principle of “guilt by association”. |
| first_indexed | 2024-03-08T14:26:10Z |
| format | Article |
| id | doaj.art-704426e33bea412993f5a6d9450d37d2 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T14:26:10Z |
| publishDate | 2024-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-704426e33bea412993f5a6d9450d37d22024-01-13T04:23:06ZengWileyAdvanced Science2198-38442024-01-01112n/an/a10.1002/advs.202305946Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, PamtidesHyunbin Lee0Sho Hee Park1Jiyoon Kim2Jaehak Lee3Min Sun Koh4Jung Ho Lee5Seokhee Kim6Department of ChemistrySeoul National University1 Gwanak‐ro, Gwanak‐guSeoul08826Republic of KoreaDepartment of ChemistrySeoul National University1 Gwanak‐ro, Gwanak‐guSeoul08826Republic of KoreaDepartment of ChemistrySeoul National University1 Gwanak‐ro, Gwanak‐guSeoul08826Republic of KoreaDepartment of ChemistrySeoul National University1 Gwanak‐ro, Gwanak‐guSeoul08826Republic of KoreaDepartment of ChemistrySeoul National University1 Gwanak‐ro, Gwanak‐guSeoul08826Republic of KoreaDepartment of ChemistrySeoul National University1 Gwanak‐ro, Gwanak‐guSeoul08826Republic of KoreaDepartment of ChemistrySeoul National University1 Gwanak‐ro, Gwanak‐guSeoul08826Republic of KoreaAbstract Ribosomally synthesized and post‐translationally modified peptides (RiPPs) are a structurally diverse class of natural products with a distinct biosynthetic logic, the enzymatic modification of genetically encoded precursor peptides. Although their structural and biosynthetic diversity remains largely underexplored, the identification of novel subclasses with unique structural motifs and biosynthetic pathways is challenging. Here, it is reported that peptide/protein L‐aspartyl O‐methyltransferases (PAMTs) present in several RiPP subclasses are highly homologous. Importantly, it is discovered that the apparent evolutionary transmission of the PAMT gene to unrelated RiPP subclasses can serve as a basis to identify a novel RiPP subclass. Biochemical and structural analyses suggest that homologous PAMTs convert aspartate to isoaspartate via aspartyl‐O‐methyl ester and aspartimide intermediates, and often require cyclic or hairpin‐like structures for modification. By conducting homology‐based bioinformatic analysis of PAMTs, over 2,800 biosynthetic gene clusters (BGCs) are identified for known RiPP subclasses in which PAMTs install a secondary modification, and over 1,500 BGCs where PAMTs function as a primary modification enzyme, thereby defining a new RiPP subclass, named pamtides. The results suggest that the genome mining of proteins with secondary biosynthetic roles can be an effective strategy for discovering novel biosynthetic pathways of RiPPs through the principle of “guilt by association”.https://doi.org/10.1002/advs.202305946genome mininggraspetidespamtidesprotein L‐(iso)aspartyl O‐methyltransferaseRiPP |
| spellingShingle | Hyunbin Lee Sho Hee Park Jiyoon Kim Jaehak Lee Min Sun Koh Jung Ho Lee Seokhee Kim Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, Pamtides Advanced Science genome mining graspetides pamtides protein L‐(iso)aspartyl O‐methyltransferase RiPP |
| title | Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, Pamtides |
| title_full | Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, Pamtides |
| title_fullStr | Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, Pamtides |
| title_full_unstemmed | Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, Pamtides |
| title_short | Evolutionary Spread of Distinct O‐methyltransferases Guides the Discovery of Unique Isoaspartate‐Containing Peptides, Pamtides |
| title_sort | evolutionary spread of distinct o methyltransferases guides the discovery of unique isoaspartate containing peptides pamtides |
| topic | genome mining graspetides pamtides protein L‐(iso)aspartyl O‐methyltransferase RiPP |
| url | https://doi.org/10.1002/advs.202305946 |
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