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RiPPS,genome mining

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https://www.readbyqxmd.com/read/28846667/klebsazolicin-inhibits-70s-ribosome-by-obstructing-the-peptide-exit-tunnel
#1
Mikhail Metelev, Ilya A Osterman, Dmitry Ghilarov, Nelli F Khabibullina, Alexander Yakimov, Konstantin Shabalin, Irina Utkina, Dmitry Y Travin, Ekaterina S Komarova, Marina Serebryakova, Tatyana Artamonova, Mikhail Khodorkovskii, Andrey L Konevega, Petr V Sergiev, Konstantin Severinov, Yury S Polikanov
Whereas screening of the small-molecule metabolites produced by most cultivatable microorganisms often results in the rediscovery of known compounds, genome-mining programs allow researchers to harness much greater chemical diversity, and result in the discovery of new molecular scaffolds. Here we report the genome-guided identification of a new antibiotic, klebsazolicin (KLB), from Klebsiella pneumoniae that inhibits the growth of sensitive cells by targeting ribosomes. A ribosomally synthesized post-translationally modified peptide (RiPP), KLB is characterized by the presence of a unique N-terminal amidine ring that is essential for its activity...
October 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28715095/a-self-sacrificing-n-methyltransferase-is-the-precursor-of-the-fungal-natural-product-omphalotin
#2
Sascha Ramm, Bartlomiej Krawczyk, Agnes Mühlenweg, Annette Poch, Eva Mösker, Roderich D Süssmuth
Research on ribosomally synthesized and posttranslationally modified peptides (RiPPs) has led to an increasing understanding of biosynthetic mechanisms, mostly drawn from bacterial examples. In contrast, reports on RiPPs from fungal producers, apart from the amanitins and phalloidins, are still scarce. The fungal cyclopeptide omphalotin A carries multiple N-methylations on the peptide backbone, a modification previously known only from nonribosomal peptides. Mining the genome of the omphalotin-producing fungus for a precursor peptide led to the identification of two biosynthesis genes, one encoding a methyltransferase OphMA that catalyzes the automethylation of its C-terminus, which is then released and cyclized by the protease OphP...
July 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28650175/bioactive-peptide-natural-products-as-lead-structures-for-medicinal-use
#3
Tam Dang, Roderich D Süssmuth
The need for new drugs for the treatment of various diseases is enormous. From the previous century until the present, numerous peptide and peptide-derived natural products have been isolated from bacteria and fungi. Hence, microorganisms play a pivotal role as sources for novel drugs with an emphasis on anti-infective agents. Various disciplines from biology, chemistry, and medicine are involved in early stages of the search for peptide natural products including taxonomy, microbiology, bioanalytics, bioinformatics, and medicinal chemistry...
June 26, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28544148/structure-and-biosynthesis-of-crocagins-polycyclic-postranslationally-modified-ribosomal-peptides-from-chondromyces-crocatus
#4
Konrad Viehrig, Frank Surup, Carsten Volz, Jennifer Herrmann, Antoine Abou Fayad, Sebastian Adam, Jesko Köhnke, Dirk Trauner, Rolf Müller
Secondary metabolome mining efforts in the myxobacterial multiproducer of natural products, Chondromyces crocatus Cm c5, resulted in the isolation and structure elucidation of crocagins, which are novel polycyclic peptides containing a tetrahydropyrrolo[2,3-b]indole core. The gene cluster was identified through an approach combining genome analysis, targeted gene inactivation in the producer, and in vitro experiments. Based on our findings, we developed a biosynthetic scheme for crocagin biosynthesis. These natural products are formed from the three C-terminal amino acids of a precursor peptide and thus belong to a novel class of ribosomally synthesized and post-translationally modified peptides (RiPPs)...
May 23, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28499008/rippminer-a-bioinformatics-resource-for-deciphering-chemical-structures-of-ripps-based-on-prediction-of-cleavage-and-cross-links
#5
Priyesh Agrawal, Shradha Khater, Money Gupta, Neetu Sain, Debasisa Mohanty
Ribosomally synthesized and post-translationally modified peptides (RiPPs) constitute a rapidly growing class of natural products with diverse structures and bioactivities. We have developed RiPPMiner, a novel bioinformatics resource for deciphering chemical structures of RiPPs by genome mining. RiPPMiner derives its predictive power from machine learning based classifiers, trained using a well curated database of more than 500 experimentally characterized RiPPs. RiPPMiner uses Support Vector Machine to distinguish RiPP precursors from other small proteins and classify the precursors into 12 sub-classes of RiPPs...
May 12, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28452467/biosynthetic-insights-into-linaridin-natural-products-from-genome-mining-and-precursor-peptide-mutagenesis
#6
Tianlu Mo, Wan-Qiu Liu, Wenjuan Ji, Junfeng Zhao, Tuo Chen, Wei Ding, Shaoning Yu, Qi Zhang
Linaridin is a small class of peptide natural products belonging to the ribosomally synthesized and post-translationally modified peptides (RiPPs) superfamily. By an extensive genome-wide survey of linaridin biosynthetic genes, we show that this class of natural products is widespread in nature and possesses vast structural diversity. The linaridin precursor peptides are relatively conserved in the N-termini but have diverse sequences in the core region, which appear to have coevolved with the biosynthetic enzymes...
June 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28260651/ribosomally-synthesized-and-post-translationally-modified-peptide-natural-product-discovery-in-the-genomic-era
#7
REVIEW
Kenton J Hetrick, Wilfred A van der Donk
In the past 15 years, the cost of sequencing a genome has plummeted. Consequently, the number of sequenced bacterial genomes has exponentially increased, and methods for natural product discovery have evolved rapidly to take advantage of the wealth of genomic data. This review highlights applications of genome mining software to compare and organize large-scale data sets and methods for identifying unique biosynthetic pathways amongst the thousands of ribosomally synthesized and post-translationally modified peptide (RiPP) gene clusters...
June 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28244986/a-new-genome-mining-tool-redefines-the-lasso-peptide-biosynthetic-landscape
#8
Jonathan I Tietz, Christopher J Schwalen, Parth S Patel, Tucker Maxson, Patricia M Blair, Hua-Chia Tai, Uzma I Zakai, Douglas A Mitchell
Ribosomally synthesized and post-translationally modified peptide (RiPP) natural products are attractive for genome-driven discovery and re-engineering, but limitations in bioinformatic methods and exponentially increasing genomic data make large-scale mining of RiPP data difficult. We report RODEO (Rapid ORF Description and Evaluation Online), which combines hidden-Markov-model-based analysis, heuristic scoring, and machine learning to identify biosynthetic gene clusters and predict RiPP precursor peptides...
May 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28210246/prospects-of-in-vivo-incorporation-of-non-canonical-amino-acids-for-the-chemical-diversification-of-antimicrobial-peptides
#9
Tobias Baumann, Jessica H Nickling, Maike Bartholomae, Andrius Buivydas, Oscar P Kuipers, Nediljko Budisa
The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of new-to-nature AMPs, and can contribute to tackle the ongoing emergence of antibiotic resistance in pathogens. Especially from a pharmacological point of view, desirable improvements span pH and protease resistance, solubility, oral availability and circulation half-life...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27998080/structure-of-the-lasso-peptide-isopeptidase-identifies-a-topology-for-processing-threaded-substrates
#10
Jonathan R Chekan, Joseph D Koos, Chuhan Zong, Mikhail O Maksimov, A James Link, Satish K Nair
Lasso peptides are a class of bioactive ribosomally synthesized and post-translationally modified peptides (RiPPs), with a threaded knot structure that is formed by an isopeptide bond attaching the N-terminus of the peptide to a side chain carboxylate. Some lasso peptide biosynthetic clusters harbor an enzyme that specifically hydrolyzes the isopeptide bond to yield the linear peptide. We describe here the 2.4 Å resolution structure of a lasso peptide isopeptidase revealing a topologically novel didomain architecture consisting of an open β-propeller appended to an α/β hydrolase domain...
December 21, 2016: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/27905614/methanobactins-from-genome-to-function
#11
Laura M K Dassama, Grace E Kenney, Amy C Rosenzweig
Methanobactins (Mbns) are ribosomally produced, post-translationally modified peptide (RiPP) natural products that bind copper with high affinity using nitrogen-containing heterocycles and thioamide groups. In some methanotrophic bacteria, Mbns are secreted under conditions of copper starvation and then re-internalized as a copper source for the enzyme particulate methane monooxygenase (pMMO). Genome mining studies have led to the identification and classification of operons encoding the Mbn precursor peptide (MbnA) as well as a number of putative transport, regulatory, and biosynthetic proteins...
January 25, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/27869143/genome-mining-unveils-widespread-natural-product-biosynthetic-capacity-in-human-oral-microbe-streptococcus-mutans
#12
Liwei Liu, Tingting Hao, Zhoujie Xie, Geoff P Horsman, Yihua Chen
Streptococcus mutans is a major pathogen causing human dental caries. As a Gram-positive bacterium with a small genome (about 2 Mb) it is considered a poor source of natural products. Due to a recent explosion in genomic data available for S. mutans strains, we were motivated to explore the natural product production potential of this organism. Bioinformatic characterization of 169 publically available genomes of S. mutans from human dental caries revealed a surprisingly rich source of natural product biosynthetic gene clusters...
November 21, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27698135/genomic-charting-of-ribosomally-synthesized-natural-product-chemical-space-facilitates-targeted-mining
#13
Michael A Skinnider, Chad W Johnston, Robyn E Edgar, Chris A Dejong, Nishanth J Merwin, Philip N Rees, Nathan A Magarvey
Microbial natural products are an evolved resource of bioactive small molecules, which form the foundation of many modern therapeutic regimes. Ribosomally synthesized and posttranslationally modified peptides (RiPPs) represent a class of natural products which have attracted extensive interest for their diverse chemical structures and potent biological activities. Genome sequencing has revealed that the vast majority of genetically encoded natural products remain unknown. Many bioinformatic resources have therefore been developed to predict the chemical structures of natural products, particularly nonribosomal peptides and polyketides, from sequence data...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27650042/deciphering-bioactive-peptides-and-their-action-mechanisms-through-proteomics
#14
Osmel Fleitas Martinez, Caleb Mawuli Agbale, Fernanda Nomiyama, Octávio Luiz Franco
Bioactive peptides such as antimicrobial peptides (AMPs), ribosomally synthesized and post translationally modified peptides (RiPPs) and the non-ribosomal peptides (NRPs) have emerged with promising applications in medicine, agriculture and industry. However, their development has been limited by several difficulties making it necessary to search for novel discovery methods. In this context, proteomics has been considered a reliable tool. Areas covered: This review highlights recent developments in proteomic tools that facilitate the discovery of AMPs, RiPPs and NRPs as well as the elucidation of action mechanisms of AMPs and resistance mechanisms of pathogens to them...
October 8, 2016: Expert Review of Proteomics
https://www.readbyqxmd.com/read/27028884/structural-characterization-and-bioactivity-analysis-of-the-two-component-lantibiotic-flv-system-from-a-ruminant-bacterium
#15
Xiling Zhao, Wilfred A van der Donk
The discovery of new ribosomally synthesized and post-translationally modified peptide natural products (RiPPs) has greatly benefitted from the influx of genomic information. The lanthipeptides are a subset of this class of compounds. Adopting the genome-mining approach revealed a novel lanthipeptide gene cluster encoded in the genome of Ruminococcus flavefaciens FD-1, an anaerobic bacterium that is an important member of the rumen microbiota of livestock. The post-translationally modified peptides were produced via heterologous expression in Escherichia coli...
February 18, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/26979951/biosynthetic-investigation-of-phomopsins-reveals-a-widespread-pathway-for-ribosomal-natural-products-in-ascomycetes
#16
Wei Ding, Wan-Qiu Liu, Youli Jia, Yongzhen Li, Wilfred A van der Donk, Qi Zhang
Production of ribosomally synthesized and posttranslationally modified peptides (RiPPs) has rarely been reported in fungi, even though organisms of this kingdom have a long history as a prolific source of natural products. Here we report an investigation of the phomopsins, antimitotic mycotoxins. We show that phomopsin is a fungal RiPP and demonstrate the widespread presence of a pathway for the biosynthesis of a family of fungal cyclic RiPPs, which we term dikaritins. We characterize PhomM as an S-adenosylmethionine-dependent α-N-methyltransferase that converts phomopsin A to an N,N-dimethylated congener (phomopsin E), and show that the methyltransferases involved in dikaritin biosynthesis have evolved differently and likely have broad substrate specificities...
March 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26462797/the-genomic-landscape-of-ribosomal-peptides-containing-thiazole-and-oxazole-heterocycles
#17
Courtney L Cox, James R Doroghazi, Douglas A Mitchell
BACKGROUND: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a burgeoning class of natural products with diverse activity that share a similar origin and common features in their biosynthetic pathways. The precursor peptides of these natural products are ribosomally produced, upon which a combination of modification enzymes installs diverse functional groups. This genetically encoded peptide-based strategy allows for rapid diversification of these natural products by mutation in the precursor genes merged with unique combinations of modification enzymes...
October 13, 2015: BMC Genomics
https://www.readbyqxmd.com/read/26402731/chaxapeptin-a-lasso-peptide-from-extremotolerant-streptomyces-leeuwenhoekii-strain-c58-from-the-hyperarid-atacama-desert
#18
Somayah S Elsayed, Franziska Trusch, Hai Deng, Andrea Raab, Ivan Prokes, Kanungnid Busarakam, Juan A Asenjo, Barbara A Andrews, Pieter van West, Alan T Bull, Michael Goodfellow, Yu Yi, Rainer Ebel, Marcel Jaspars, Mostafa E Rateb
Lasso peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that possess a unique "lariat knot" structural motif. Genome mining-targeted discovery of new natural products from microbes obtained from extreme environments has led to the identification of a gene cluster directing the biosynthesis of a new lasso peptide, designated as chaxapeptin 1, in the genome of Streptomyces leeuwenhoekii strain C58 isolated from the Atacama Desert. Subsequently, 1 was isolated and characterized using high-resolution electrospray ionization mass spectrometry and nuclear magnetic resonance methods...
October 16, 2015: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/26079760/lasso-peptides-an-intriguing-class-of-bacterial-natural-products
#19
REVIEW
Julian D Hegemann, Marcel Zimmermann, Xiulan Xie, Mohamed A Marahiel
Natural products of peptidic origin often represent a rich source of medically relevant compounds. The synthesis of such polypeptides in nature is either initiated by deciphering the genetic code on the ribosome during the translation process or driven by ribosome-independent processes. In the latter case, highly modified bioactive peptides are assembled by multimodular enzymes designated as nonribosomal peptide synthetases (NRPS) that act as a protein-template to generate chemically diverse peptides. On the other hand, the ribosome-dependent strategy, although relying strictly on the 20-22 proteinogenic amino acids, generates structural diversity by extensive post-translational-modification...
July 21, 2015: Accounts of Chemical Research
https://www.readbyqxmd.com/read/26006047/facile-removal-of-leader-peptides-from-lanthipeptides-by-incorporation-of-a-hydroxy-acid
#20
Noah A Bindman, Silvia C Bobeica, Wenshe R Liu, Wilfred A van der Donk
The biosynthesis of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products typically involves a precursor peptide which contains a leader peptide that is important for the modification process, and that is removed in the final step by a protease. Genome mining efforts for new RiPPs are often hampered by the lack of a general method to remove the leader peptides. We describe here the incorporation of hydroxy acids into the precursor peptides in E. coli which results in connection of the leader peptide via an ester linkage that is readily cleaved by simple hydrolysis...
June 10, 2015: Journal of the American Chemical Society
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