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  • 1
    Publication Date: 2012-09-18
    Description: It is held as a paradigm that ribosomally synthesized peptides and proteins contain only l-amino acids. We demonstrate a ribosomal origin of the marine sponge-derived polytheonamides, exceptionally potent, giant natural-product toxins. Isolation of the biosynthetic genes from the sponge metagenome revealed a bacterial gene architecture. Only six candidate enzymes were identified for 48 posttranslational modifications, including 18 epimerizations and 17 methylations of nonactivated carbon centers. Three enzymes were functionally validated, which showed that a radical S-adenosylmethionine enzyme is responsible for the unidirectional epimerization of multiple and different amino acids. Collectively, these complex alterations create toxins that function as unimolecular minimalistic ion channels with near-femtomolar activity. This study broadens the biosynthetic scope of ribosomal systems and creates new opportunities for peptide and protein bioengineering.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Freeman, Michael F -- Gurgui, Cristian -- Helf, Maximilian J -- Morinaka, Brandon I -- Uria, Agustinus R -- Oldham, Neil J -- Sahl, Hans-Georg -- Matsunaga, Shigeki -- Piel, Jorn -- New York, N.Y. -- Science. 2012 Oct 19;338(6105):387-90. doi: 10.1126/science.1226121. Epub 2012 Sep 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Kekule Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22983711" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Ion Channels/biosynthesis/*metabolism ; Marine Toxins/biosynthesis/*metabolism ; *Metagenome ; Methylation ; Molecular Sequence Data ; Protein Biosynthesis ; *Protein Processing, Post-Translational ; Proteins/*metabolism ; Ribosomes/metabolism ; S-Adenosylmethionine/metabolism ; Theonella/*microbiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-01-31
    Description: Cultivated bacteria such as actinomycetes are a highly useful source of biomedically important natural products. However, such 'talented' producers represent only a minute fraction of the entire, mostly uncultivated, prokaryotic diversity. The uncultured majority is generally perceived as a large, untapped resource of new drug candidates, but so far it is unknown whether taxa containing talented bacteria indeed exist. Here we report the single-cell- and metagenomics-based discovery of such producers. Two phylotypes of the candidate genus 'Entotheonella' with genomes of greater than 9 megabases and multiple, distinct biosynthetic gene clusters co-inhabit the chemically and microbially rich marine sponge Theonella swinhoei. Almost all bioactive polyketides and peptides known from this animal were attributed to a single phylotype. 'Entotheonella' spp. are widely distributed in sponges and belong to an environmental taxon proposed here as candidate phylum 'Tectomicrobia'. The pronounced bioactivities and chemical uniqueness of 'Entotheonella' compounds provide significant opportunities for ecological studies and drug discovery.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilson, Micheal C -- Mori, Tetsushi -- Ruckert, Christian -- Uria, Agustinus R -- Helf, Maximilian J -- Takada, Kentaro -- Gernert, Christine -- Steffens, Ursula A E -- Heycke, Nina -- Schmitt, Susanne -- Rinke, Christian -- Helfrich, Eric J N -- Brachmann, Alexander O -- Gurgui, Cristian -- Wakimoto, Toshiyuki -- Kracht, Matthias -- Crusemann, Max -- Hentschel, Ute -- Abe, Ikuro -- Matsunaga, Shigeki -- Kalinowski, Jorn -- Takeyama, Haruko -- Piel, Jorn -- England -- Nature. 2014 Feb 6;506(7486):58-62. doi: 10.1038/nature12959. Epub 2014 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Microbiology, Eidgenossische Technische Hochschule Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland [2] Kekule Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany [3]. ; 1] Faculty of Science and Engineering, Waseda University Center for Advanced Biomedical Sciences, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan [2]. ; Institute for Genome Research and Systems Biology, Center for Biotechnology, Universitat Bielefeld, Universitatstrasse 25, 33594 Bielefeld, Germany. ; 1] Institute of Microbiology, Eidgenossische Technische Hochschule Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland [2] Kekule Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany. ; Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. ; Department of Botany II, Julius-von-Sachs Institute for Biological Sciences, University of Wurzburg, Julius-von-Sachs-Platz 3, 97082 Wurzburg, Germany. ; Kekule Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany. ; Department of Earth and Environmental Sciences, Palaeontology and Geobiology, Ludwig Maximilians University Munich, Richard-Wagner-Strasse 10, 80333 Munich, Germany. ; Department of Energy Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA. ; Institute of Microbiology, Eidgenossische Technische Hochschule Zurich, Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland. ; Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; Faculty of Science and Engineering, Waseda University Center for Advanced Biomedical Sciences, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24476823" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biosynthetic Pathways/genetics ; Deltaproteobacteria/*classification/genetics/*metabolism/physiology ; *Drug Discovery ; Environmental Microbiology ; Genes, Bacterial/genetics ; Genome, Bacterial/genetics ; Metagenomics ; Molecular Sequence Data ; Multigene Family/genetics ; Peptides/metabolism ; Polyketides/metabolism ; Porifera/metabolism/microbiology ; Single-Cell Analysis ; Symbiosis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-02-16
    Description: Current textbook knowledge holds that the structural scope of ribosomal biosynthesis is based exclusively on α-amino acid backbone topology. Here we report the genome-guided discovery of bacterial pathways that posttranslationally create β-amino acid–containing products. The transformation is widespread in bacteria and is catalyzed by an enzyme belonging to a previously uncharacterized radical S -adenosylmethionine family. We show that the β-amino acids result from an unusual protein splicing process involving backbone carbon-carbon bond cleavage and net excision of tyramine. The reaction can be used to incorporate diverse and multiple β-amino acids into genetically encoded precursors in Escherichia coli . In addition to enlarging the set of basic amino acid components, the excision generates keto functions that are useful as orthogonal reaction sites for chemical diversification.
    Keywords: Microbiology, Molecular Biology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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