Genome mining has become a key technology to exploit natural product diversity. While initially performed on a single-genome basis, the process is now being scaled up to mine entire genera, strain collections and microbiomes. However, no bioinformatic framework is currently available for effectively analyzing datasets of this size and complexity. Here, we provide a streamlined computational workflow consisting of two new software tools: The 'Biosynthetic Gene Similarity Clustering And Prospecting Engine' (BiG-SCAPE) facilitates fast and interactive sequence similarity network analysis of biosynthetic gene clusters and gene cluster families. 'CORe Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Highly oxygenated multifunctional organic compounds (HOMs) originating from biogenic emissions constitute a widespread source of organic aerosols in the pristine atmosphere. However, the molecular forms in which HOMs are present in the condensed phase upon gas-particle partitioning remain unclear. In this study, we show that highly oxygenated molecules that contain multiple peroxide functionalities are readily cationized by the attachment of Na during electrospray ionization operated in the positive ion mode. With this method, we present the first identification of HOMs characterized as CHO monomers and CHO dimers in α-pinene derived secondary organic aerosol (SOA). Simultaneous detection of these molecules in the gas phase provides direct evidence for their gas-to-particle conversion. Molecular properties of particulate HOMs generated from ozonolysis and OH oxidation of unsubstituted (CH) and deuterated (CHD) α-pinene are investigated using coupled ion mobility spectrometry with mass spectrometry. The systematic shift in the mass of monomers in the deuterated system is consistent with the decomposition of isomeric vinylhydroperoxides to release vinoxy radical isotopologues, the precursors to a sequence of autoxidation reactions that ultimately yield HOMs in the gas phase. The remarkable difference observed in the dimer abundance under O- versus OH-dominant environments underlines the competition between intramolecular hydrogen migration of peroxy radicals and their bimolecular termination reactions. Our results provide new and direct molecular-level information for a key component needed for achieving carbon mass closure of α-pinene SOA.
The prodiginine family of bacterial alkaloids is a diverse set of heterocyclic natural products that have likely been known to man since antiquity. In more recent times, these alkaloids have been discovered to span a wide range of chemical structures that possess a number of interesting biological activities. This review provides a comprehensive overview of research undertaken toward the isolation and structural elucidation of the prodiginine family of natural products. Additionally, research toward chemical synthesis of the prodiginine alkaloids over the last several decades is extensively reviewed. Finally, the current, evidence-based understanding of the various biosynthetic pathways employed by bacteria to produce prodiginine alkaloids is summarized.
For more than half a century the pharmaceutical industry has sifted through natural products produced by microbes, uncovering new scaffolds and fashioning them into a broad range of vital drugs. We sought a strategy to reinvigorate the discovery of natural products with distinctive structures using bacterial genome sequencing combined with metabolomics. By correlating genetic content from 178 actinomycete genomes with mass spectrometry-enabled analyses of their exported metabolomes, we paired new secondary metabolites with their biosynthetic gene clusters. We report the use of this new approach to isolate and characterize tambromycin, a new chlorinated natural product, composed of several nonstandard amino acid monomeric units, including a unique pyrrolidine-containing amino acid we name tambroline. Tambromycin shows antiproliferative activity against cancerous human B- and T-cell lines. The discovery of tambromycin via large-scale correlation of gene clusters with metabolites (a.k.a. metabologenomics) illuminates a path for structure-based discovery of natural products at a sharply increased rate.
Genome mining has become a key technology to explore and exploit natural product diversity through the identification and analysis of biosynthetic gene clusters (BGCs). Initially, this was performed on a single-genome basis; currently, the process is being scaled up to large-scale mining of pan-genomes of entire genera, complete strain collections and metagenomic datasets from which thousands of bacterial genomes can be extracted at once. However, no bioinformatic framework is currently available for the effective analysis of datasets of this size and complexity. Here, we provide a streamlined computational workflow, tightly integrated with antiSMASH and MIBiG, that consists of two new software tools, BiG-SCAPE and CORASON. BiG-SCAPE facilitates rapid calculation and interactive visual exploration of BGC sequence similarity networks, grouping gene clusters at multiple hierarchical levels, and includes a 'glocal' alignment mode that accurately groups both complete and fragmented BGCs. CORASON employs a phylogenomic approach to elucidate the detailed evolutionary relationships between gene clusters by computing high-resolution multi-locus phylogenies of all BGCs within and across gene cluster families (GCFs), and allows researchers to comprehensively identify all genomic contexts in which particular biosynthetic gene cassettes are found. We validate BiG-SCAPE by correlating its GCF output to metabolomic data across 403 actinobacterial strains. Furthermore, we demonstrate the discovery potential of the platform by using CORASON to comprehensively map the phylogenetic diversity of the large detoxin/rimosamide gene cluster clan, prioritizing three new detoxin families for subsequent characterization of six new analogs using isotopic labeling and analysis of tandem mass spectrometric data.
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