{"title":"香豆素笼多肽的光克莱森重排导致令人惊讶的酶超活化。","authors":"Corina Maller, Eirini Marouda, Maja Köhn","doi":"10.1002/cbic.202400561","DOIUrl":null,"url":null,"abstract":"<p>Protein phosphatase-1 (PP1) is a ubiquitous enzyme that counteracts hundreds of kinases in cells. PP1 interacts with regulatory proteins via an <i>RVxF</i> peptide motif that binds to a hydrophobic groove on the enzyme. PP1-disrupting peptides (PDPs) compete with these regulatory proteins, leading to the release of the active PP1 subunit and promoting substrate dephosphorylation. Building on previous strategies employing the <i>ortho</i>-nitrobenzyl (<i>o</i>-Nb) group as a photocage to control PDP activity, we introduced coumarin derivatives into a PDP via an ether bond to explore their effects on PP1 activity. Surprisingly, our study revealed that the coumarin-caged peptides (PDP-DEACM and PDP-CM) underwent a photo-Claisen rearrangement, resulting in an unexpected hyperactivation of PP1. Our findings underscore the importance of linker design in controlling uncaging efficiency of photocages and highlight the need for comprehensive <i>in vitro</i> analysis before cellular experiments.</p>","PeriodicalId":140,"journal":{"name":"ChemBioChem","volume":"25 22","pages":""},"PeriodicalIF":2.6000,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202400561","citationCount":"0","resultStr":"{\"title\":\"Photo-Claisen Rearrangement in a Coumarin-Caged Peptide Leads to a Surprising Enzyme Hyperactivation\",\"authors\":\"Corina Maller, Eirini Marouda, Maja Köhn\",\"doi\":\"10.1002/cbic.202400561\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Protein phosphatase-1 (PP1) is a ubiquitous enzyme that counteracts hundreds of kinases in cells. PP1 interacts with regulatory proteins via an <i>RVxF</i> peptide motif that binds to a hydrophobic groove on the enzyme. PP1-disrupting peptides (PDPs) compete with these regulatory proteins, leading to the release of the active PP1 subunit and promoting substrate dephosphorylation. Building on previous strategies employing the <i>ortho</i>-nitrobenzyl (<i>o</i>-Nb) group as a photocage to control PDP activity, we introduced coumarin derivatives into a PDP via an ether bond to explore their effects on PP1 activity. Surprisingly, our study revealed that the coumarin-caged peptides (PDP-DEACM and PDP-CM) underwent a photo-Claisen rearrangement, resulting in an unexpected hyperactivation of PP1. Our findings underscore the importance of linker design in controlling uncaging efficiency of photocages and highlight the need for comprehensive <i>in vitro</i> analysis before cellular experiments.</p>\",\"PeriodicalId\":140,\"journal\":{\"name\":\"ChemBioChem\",\"volume\":\"25 22\",\"pages\":\"\"},\"PeriodicalIF\":2.6000,\"publicationDate\":\"2024-08-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cbic.202400561\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ChemBioChem\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/cbic.202400561\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ChemBioChem","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/cbic.202400561","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Photo-Claisen Rearrangement in a Coumarin-Caged Peptide Leads to a Surprising Enzyme Hyperactivation
Protein phosphatase-1 (PP1) is a ubiquitous enzyme that counteracts hundreds of kinases in cells. PP1 interacts with regulatory proteins via an RVxF peptide motif that binds to a hydrophobic groove on the enzyme. PP1-disrupting peptides (PDPs) compete with these regulatory proteins, leading to the release of the active PP1 subunit and promoting substrate dephosphorylation. Building on previous strategies employing the ortho-nitrobenzyl (o-Nb) group as a photocage to control PDP activity, we introduced coumarin derivatives into a PDP via an ether bond to explore their effects on PP1 activity. Surprisingly, our study revealed that the coumarin-caged peptides (PDP-DEACM and PDP-CM) underwent a photo-Claisen rearrangement, resulting in an unexpected hyperactivation of PP1. Our findings underscore the importance of linker design in controlling uncaging efficiency of photocages and highlight the need for comprehensive in vitro analysis before cellular experiments.
期刊介绍:
ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).