scholarly journals A new genome-mining tool redefines the lasso peptide biosynthetic landscape

2017 ◽  
Vol 13 (5) ◽  
pp. 470-478 ◽  
Author(s):  
Jonathan I Tietz ◽  
Christopher J Schwalen ◽  
Parth S Patel ◽  
Tucker Maxson ◽  
Patricia M Blair ◽  
...  
Keyword(s):  
Genome Mining ◽  
Lasso Peptide ◽  
Mining Tool

scholarly journals Discovery of the Class I Antimicrobial Lasso Peptide Arcumycin

2021 ◽  
Author(s):  
Lydia Stariha ◽  
Dewey G. McCafferty
Keyword(s):  
Micrococcus Luteus ◽  
Genome Mining ◽  
Antibiotic Activity ◽  
Peptide Sequence ◽  
Class I ◽  
Gram Positive ◽  
Conformationally Constrained ◽  
Lasso Peptide ◽  
Lasso Peptides ◽  
Lipid Ii

<p>Lasso peptides are a structurally diverse superfamily of</p><p>conformationally-constrained peptide natural products, of which a</p><p>subset exhibits broad antimicrobial activity. Although advances in</p><p>bioinformatics have increased our knowledge of strains harboring</p><p>the biosynthetic machinery for lasso peptide production, relating</p><p>peptide sequence to bioactivity remains a continuous challenge.</p><p>Towards this end, a structure-driven genome mining investigation</p><p>of Actinobacteria-produced antimicrobial lasso peptides was</p><p>performed to correlate predicted primary structure with antibiotic</p><p>activity. Bioinformatic evaluation revealed eight putative novel</p><p>class I lasso peptide sequences. This subset is predicted to</p><p>possess antibiotic activity as characterized members of this class</p><p>have both broad spectrum and potent activity against Gram positive</p><p>strains. Fermentation of one of these hits, Streptomyces</p><p>NRRL F-5639, resulted in the production of a novel class I lasso</p><p>peptide, arcumycin, named for the Latin word for bow or arch,</p><p>arcum. Arcumycin exhibited antibiotic activity against Gram positive</p><p>bacteria including <i>Bacillus subtilis</i> (4 μg/mL),</p><p><i>Staphylococcus aureus </i>(8 μg/mL), and <i>Micrococcus luteus</i> (8</p><p>μg/mL). Arcumycin treatment of <i>B. subtilis</i> liaI-β-gal promoter</p><p>fusion reporter strain resulted in upregulation of the system liaRS</p><p>by the promoter liaI, indicating arcumycin interferes with lipid II</p><p>biosynthesis. Cumulatively, the results illustrate the relationship</p><p>between phylogenetically related lasso peptides and their</p><p>bioactivity as validated through the isolation, structural</p><p>determination, and evaluation of bioactivity of the novel class I</p><p>antimicrobial lasso peptide arcumycin.</p>

scholarly journals Uncovering the unexplored diversity of thioamidated ribosomal peptides in Actinobacteria using the RiPPER genome mining tool

2018 ◽  
Author(s):  
Javier Santos-Aberturas ◽  
Govind Chandra ◽  
Luca Frattaruolo ◽  
Rodney Lacret ◽  
Thu H. Pham ◽  
...  
Keyword(s):  
Genome Mining ◽  
Gene Clusters ◽  
Chemical Diversity ◽  
Bioactive Molecules ◽  
Post Translational Modification ◽  
Biosynthetic Gene Clusters ◽  
New Family ◽  
The Family ◽  
Modified Peptides ◽  
Mining Tool

ABSTRACTThe rational discovery of new specialized metabolites by genome mining represents a very promising strategy in the quest for new bioactive molecules. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural product that derive from genetically encoded precursor peptides. However, RiPP gene clusters are particularly refractory to reliable bioinformatic predictions due to the absence of a common biosynthetic feature across all pathways. Here, we describe RiPPER, a new tool for the family-independent identification of RiPP precursor peptides and apply this methodology to search for novel thioamidated RiPPs in Actinobacteria. Until now, thioamidation was believed to be a rare post-translational modification, which is catalyzed by a pair of proteins (YcaO and TfuA) in Archaea. In Actinobacteria, the thioviridamide-like molecules are a family of cytotoxic RiPPs that feature multiple thioamides, and it has been proposed that a YcaO-TfuA pair of proteins also catalyzes their formation. Potential biosynthetic gene clusters encoding YcaO and TfuA protein pairs are common in Actinobacteria but the chemical diversity generated by these pathways is almost completely unexplored. A RiPPER analysis reveals a highly diverse landscape of precursor peptides encoded in previously undescribed gene clusters that are predicted to make thioamidated RiPPs. To illustrate this strategy, we describe the first rational discovery of a new family of thioamidated natural products, the thiovarsolins from Streptomyces varsoviensis.

scholarly journals RRE-Finder: a Genome-Mining Tool for Class-Independent RiPP Discovery

mSystems ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Alexander M. Kloosterman ◽  
Kyle E. Shelton ◽  
Gilles P. van Wezel ◽  
Marnix H. Medema ◽  
Douglas A. Mitchell
Keyword(s):  
Structure Prediction ◽  
Secondary Structure Prediction ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene Clusters ◽  
High Confidence ◽  
Genetic Feature ◽  
Uniprotkb Database ◽  
A Genome ◽  
Mining Tool

Bioinformatics-powered discovery of novel ribosomal natural products (RiPPs) has historically been hindered by the lack of a common genetic feature across RiPP classes. Herein, we introduce RRE-Finder, a method for identifying RRE domains, which are present in a majority of prokaryotic RiPP biosynthetic gene clusters (BGCs). RRE-Finder identifies RRE domains 3,000 times faster than current methods, which rely on time-consuming secondary structure prediction. Depending on user goals, RRE-Finder can operate in precision mode to accurately identify RREs present in known RiPP classes or in exploratory mode to assist with novel RiPP discovery. Employing RRE-Finder on the UniProtKB database revealed several high-confidence RREs in novel RiPP-like clusters, suggesting that many new RiPP classes remain to be discovered.

Heterologous production of new lasso peptide koreensin based on genome mining

2020 ◽  
Vol 74 (1) ◽  
pp. 42-50
Author(s):  
Hiroki Fuwa ◽  
Hikaru Hemmi ◽  
Issara Kaweewan ◽  
Ikko Kozaki ◽  
Hiroyuki Honda ◽  
...  
Keyword(s):  
Genome Mining ◽  
Heterologous Production ◽  
Lasso Peptide

scholarly journals Discovery and characterisation of an amidine-containing ribosomally-synthesised peptide that is widely distributed in nature

2020 ◽  
Author(s):  
Alicia H. Russell ◽  
Natalia M. Vior ◽  
Edward S. Hems ◽  
Rodney Lacret ◽  
Andrew W. Truman
Keyword(s):  
Natural Product ◽  
Genome Mining ◽  
Gene Clusters ◽  
Model Organisms ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Post Translational Modifications ◽  
Streptomyces Albus ◽  
Modified Peptides ◽  
Mining Tool

ABSTRACTRibosomally synthesised and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural product with a range of bioactivities. Genome mining for RiPP biosynthetic gene clusters (BGCs) is often hampered by poor detection of the short precursor peptides that are ultimately modified into the final molecule. Here, we utilise a previously described genome mining tool, RiPPER, to identify novel RiPP precursor peptides near YcaO-domain proteins, enzymes that catalyse various RiPP post-translational modifications including heterocyclisation and thioamidation. Using this dataset, we identified a novel, diverse and highly conserved family of RiPP BGCs spanning over 230 species of Actinobacteria and Firmicutes. A representative BGC from Streptomyces albus J1074 was characterised, leading to the discovery of streptamidine, a novel-amidine containing RiPP. This highlights the breadth of unexplored natural products with structurally rare features, even in model organisms.

scholarly journals Uncovering the unexplored diversity of thioamidated ribosomal peptides in Actinobacteria using the RiPPER genome mining tool

2019 ◽  
Vol 47 (9) ◽  
pp. 4624-4637 ◽  
Author(s):  
Javier Santos-Aberturas ◽  
Govind Chandra ◽  
Luca Frattaruolo ◽  
Rodney Lacret ◽  
Thu H Pham ◽  
...  
Keyword(s):  
Genome Mining ◽  
Mining Tool

Isolation and structure determination of a new lasso peptide specialicin based on genome mining

2018 ◽  
Vol 26 (23-24) ◽  
pp. 6050-6055 ◽  
Author(s):  
Issara Kaweewan ◽  
Hikaru Hemmi ◽  
Hisayuki Komaki ◽  
Shigeyoshi Harada ◽  
Shinya Kodani
Keyword(s):  
Structure Determination ◽  
Genome Mining ◽  
Lasso Peptide

scholarly journals Bioinformatic and Reactivity-Based Discovery of Linaridins

2020 ◽  
Author(s):  
Matthew A. Georgiou ◽  
Shravan R. Dommaraju ◽  
Xiaorui Guo ◽  
Douglas A. Mitchell
Keyword(s):  
Natural Product ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene Clusters ◽  
Road Map ◽  
Streptomyces Noursei ◽  
A Genome ◽  
Powerful Approach ◽  
Mining Tool ◽  
Future Work

AbstractLinaridins are members of the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products. Five linaridins have been reported, which are defined by the presence of dehydrobutyrine, a dehydrated threonine residue. This work describes the development of a linaridin specific scoring module for Rapid ORF Description and Evaluation Online (RODEO), a genome-mining tool tailored towards RiPP discovery. Upon mining publicly accessible genomes available in the NCBI database, RODEO identified 561 (382 non-redundant) linaridin biosynthetic gene clusters (BGCs). Linaridin BGCs with unique gene architectures and precursor sequences markedly different from previous predictions were uncovered during these efforts. To aid in dataset validation, two new linaridins, pegvadin A and B, were detected through reactivity-based screening (RBS) and isolated from Streptomyces noursei and Streptomyces auratus, respectively. RBS involves the use of a reactive chemical probe that chemoselectively modifies a functional group present in the natural product. The dehydrated amino acids present in linaridins as α/β-unsaturated carbonyls were appropriate electrophiles for nucleophilic 1,4 addition using a thiol-functionalized probe. The data presented within significantly expands the number of predicted linaridin BGCs and serves as a road map for future work in the area. The combination of bioinformatics and RBS is a powerful approach to accelerate natural product discovery.

scholarly journals Precursor-centric genome-mining approach for lasso peptide discovery

2012 ◽  
Vol 109 (38) ◽  
pp. 15223-15228 ◽  
Author(s):  
Mikhail O. Maksimov ◽  
István Pelczer ◽  
A. James Link
Keyword(s):  
Solution Structure ◽  
Caulobacter Crescentus ◽  
Genome Mining ◽  
Gene Clusters ◽  
Bacterial Phyla ◽  
Lasso Peptide ◽  
Lasso Peptides ◽  
Genes Encoding ◽  
Peptide Gene ◽  
Conserved Amino Acids

Lasso peptides are a class of ribosomally synthesized posttranslationally modified natural products found in bacteria. Currently known lasso peptides have a diverse set of pharmacologically relevant activities, including inhibition of bacterial growth, receptor antagonism, and enzyme inhibition. The biosynthesis of lasso peptides is specified by a cluster of three genes encoding a precursor protein and two enzymes. Here we develop a unique genome-mining algorithm to identify lasso peptide gene clusters in prokaryotes. Our approach involves pattern matching to a small number of conserved amino acids in precursor proteins, and thus allows for a more global survey of lasso peptide gene clusters than does homology-based genome mining. Of more than 3,000 currently sequenced prokaryotic genomes, we found 76 organisms that are putative lasso peptide producers. These organisms span nine bacterial phyla and an archaeal phylum. To provide validation of the genome-mining method, we focused on a single lasso peptide predicted to be produced by the freshwater bacterium Asticcacaulis excentricus. Heterologous expression of an engineered, minimal gene cluster in Escherichia coli led to the production of a unique lasso peptide, astexin-1. At 23 aa, astexin-1 is the largest lasso peptide isolated to date. It is also highly polar, in contrast to many lasso peptides that are primarily hydrophobic. Astexin-1 has modest antimicrobial activity against its phylogenetic relative Caulobacter crescentus. The solution structure of astexin-1 was determined revealing a unique topology that is stabilized by hydrogen bonding between segments of the peptide.

scholarly journals Albusnodin: an acetylated lasso peptide fromStreptomyces albus

2018 ◽  
Vol 54 (11) ◽  
pp. 1339-1342 ◽  
Author(s):  
Chuhan Zong ◽  
Wai Ling Cheung-Lee ◽  
Hader E. Elashal ◽  
Monika Raj ◽  
A. James Link
Keyword(s):  
Heterologous Expression ◽  
Genome Mining ◽  
Post Translational Modification ◽  
Lasso Peptide

Genome mining and heterologous expression has revealed a new lasso peptide, albusnodin, with an obligate acetyllysine post-translational modification.

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