scholarly journals GRINS: Genetic elements that recode assembly-line polyketide synthases and accelerate their diversification

2021 ◽  
Vol 118 (26) ◽  
pp. e2100751118 ◽  
Author(s):  
Aleksandra Nivina ◽  
Sur Herrera Paredes ◽  
Hunter B. Fraser ◽  
Chaitan Khosla
Keyword(s):  
Molecular Mechanisms ◽  
Assembly Line ◽  
Gene Families ◽  
Gene Clusters ◽  
Nucleotide Composition ◽  
Polyketide Synthases ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Bacterial Phyla ◽  
Genetic Elements

Assembly-line polyketide synthases (PKSs) are large and complex enzymatic machineries with a multimodular architecture, typically encoded in bacterial genomes by biosynthetic gene clusters. Their modularity has led to an astounding diversity of biosynthesized molecules, many with medical relevance. Thus, understanding the mechanisms that drive PKS evolution is fundamental for both functional prediction of natural PKSs as well as for the engineering of novel PKSs. Here, we describe a repetitive genetic element in assembly-line PKS genes which appears to play a role in accelerating the diversification of closely related biosynthetic clusters. We named this element GRINS: genetic repeats of intense nucleotide skews. GRINS appear to recode PKS protein regions with a biased nucleotide composition and to promote gene conversion. GRINS are present in a large number of assembly-line PKS gene clusters and are particularly widespread in the actinobacterial genus Streptomyces. While the molecular mechanisms associated with GRINS appearance, dissemination, and maintenance are unknown, the presence of GRINS in a broad range of bacterial phyla and gene families indicates that these genetic elements could play a fundamental role in protein evolution.

scholarly journals Unraveling the iterative type I polyketide synthases hidden in Streptomyces

2020 ◽  
Vol 117 (15) ◽  
pp. 8449-8454 ◽  
Author(s):  
Bin Wang ◽  
Fang Guo ◽  
Chunshuai Huang ◽  
Huimin Zhao
Keyword(s):  
Assembly Line ◽  
Gene Clusters ◽  
Polyketide Synthases ◽  
Type I ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Computational Tools ◽  
End Products ◽  
Fungal Natural Products ◽  
Biased Distribution

Type I polyketide synthases (T1PKSs) are one of the most extensively studied PKSs, which can act either iteratively or via an assembly-line mechanism. Domains in the T1PKSs can readily be predicted by computational tools based on their highly conserved sequences. However, to distinguish between iterative and noniterative at the module level remains an overwhelming challenge, which may account for the seemingly biased distribution of T1PKSs in fungi and bacteria: small iterative monomodular T1PKSs that are responsible for the enormously diverse fungal natural products exist almost exclusively in fungi. Here we report the discovery of iterative T1PKSs that are unexpectedly both abundant and widespread in Streptomyces. Seven of 11 systematically selected T1PKS monomodules from monomodular T1PKS biosynthetic gene clusters (BGCs) were experimentally confirmed to be iteratively acting, synthesizing diverse branched/nonbranched linear intermediates, and two of them produced bioactive allenic polyketides and citreodiols as end products, respectively. This study indicates the huge potential of iterative T1PKS BGCs from streptomycetes in the discovery of novel polyketides.

scholarly journals Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues

2020 ◽  
Author(s):  
Sandra A. C. Figueiredo ◽  
Marco Preto ◽  
Gabriela Moreira ◽  
Teresa P. Martins ◽  
Kathleen Abt ◽  
...  
Keyword(s):  
Natural Products ◽  
Fatty Acid ◽  
Isotope Labeling ◽  
Gene Clusters ◽  
New Drugs ◽  
Beta Oxidation ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Apparent Lack ◽  
Massive Sequencing

Natural products have an important role in several human activities, most notably as sources of new drugs. In recent years, massive sequencing and annotation of bacterial genomes has revealed an unexpectedly large number of secondary metabolite biosynthetic gene clusters whose products are yet to be discovered. For example, cyanobacterial genomes contain a large number of gene clusters that likely incorporate fatty acid-derived moieties, but for most cases we lack the knowledge and tools to effectively predict or detect the encoded natural products. Here, we exploit the apparent lack of a functional beta-oxidation pathway in cyanobacteria to achieve efficient stable-isotope labeling of their fatty acid-derived lipidome. We show that supplementation of cyanobacterial cultures with deuterated fatty acids can be used to easily detect natural product signatures in individual strains. The utility of this strategy is demonstrated in two cultured cyanobacteria by uncovering analogues of the multidrug-resistance reverting hapalosin, and novel, cytotoxic, lactylate-nocuolin A hybrids – the nocuolactylates.

scholarly journals A global survey of specialized metabolic diversity encoded in bacterial genomes

2021 ◽  
Author(s):  
Athina Gavriilidou ◽  
Satria A Kautsar ◽  
Nestor Zaburannyi ◽  
Daniel Krug ◽  
Rolf Mueller ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Evolutionary History ◽  
Gene Clusters ◽  
Chemical Diversity ◽  
Metabolic Diversity ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Taxonomic Rank ◽  
New Antibiotics ◽  
Biosynthetic Machinery

Bacterial secondary metabolites have been studied for decades for their usefulness as drugs, such as antibiotics. However, the identification of new structures has been decelerating, in part due to rediscovery of known compounds. Meanwhile, multi-resistant pathogens continue to emerge, urging the need for new antibiotics. It is unclear how much chemical diversity exists in Nature and whether discovery efforts should be focused on established antibiotic producers or rather on understudied taxa. Here, we surveyed around 170,000 bacterial genomes as well as several thousands of Metagenome Assembled Genomes (MAGs) for their diversity in Biosynthetic Gene Clusters (BGCs) known to encode the biosynthetic machinery for producing secondary metabolites. We used two distinct algorithms to provide a global overview of the biosynthetic diversity present in the sequenced part of the bacterial kingdom. Our results indicate that only 3% of genomic potential for natural products has been experimentally discovered. We connect the emergence of most biosynthetic diversity in evolutionary history close to the taxonomic rank of genus. Despite enormous differences in potential among taxa, we identify Streptomyces as by far the most biosynthetically diverse based on currently available data. Simultaneously, our analysis highlights multiple promising high-producing taxas that have thus far escaped investigation.

Structure, Synthesis of Hierridin C and Discovery of Prevalent Alkylresorcinol Biosynthesis in Picocyanobacteria

2018 ◽  
Author(s):  
Margarida Costa ◽  
Ivo E. Sampaio-Dias ◽  
Raquel Castelo-Branco ◽  
Hugo Scharfenstein ◽  
Roberta Rezende de Castro ◽  
...  
Keyword(s):  
Structure Elucidation ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Synthetic Route ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Type Iii ◽  
Structure Synthesis ◽  
Globally Distributed

Small, single-celled planktonic cyanobacteria are ubiquitous in the world’s oceans yet tend not to to be perceived as biosynthetically-prolific organisms. Here we report the isolation and structure elucidation of hierridin C, an antiplasmodial halogenated alkylresorcinol produced in very low amounts by the picocyanobacterium <i>Cyanobium</i>sp. LEGE 06113. We describe a simple, straightforward synthetic route to the scarcely-produced hierridins that relies on a key, highly regioselective halogenation step. In addition, we show that these compounds originate from a type III PKS pathway and that similar biosynthetic gene clusters are found in a variety of bacterial genomes, most notably those of the globally-distributed picocyanobacteria genera <i>Prochlorococcus</i>, <i>Cyanobium</i>and <i>Synechococcus</i>.

scholarly journals Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues

2020 ◽  
Author(s):  
Sandra A. C. Figueiredo ◽  
Marco Preto ◽  
Gabriela Moreira ◽  
Teresa P. Martins ◽  
Kathleen Abt ◽  
...  
Keyword(s):  
Natural Products ◽  
Fatty Acid ◽  
Isotope Labeling ◽  
Gene Clusters ◽  
New Drugs ◽  
Beta Oxidation ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Apparent Lack ◽  
Massive Sequencing

Natural products have an important role in several human activities, most notably as sources of new drugs. In recent years, massive sequencing and annotation of bacterial genomes has revealed an unexpectedly large number of secondary metabolite biosynthetic gene clusters whose products are yet to be discovered. For example, cyanobacterial genomes contain a large number of gene clusters that likely incorporate fatty acid-derived moieties, but for most cases we lack the knowledge and tools to effectively predict or detect the encoded natural products. Here, we exploit the apparent lack of a functional beta-oxidation pathway in cyanobacteria to achieve efficient stable-isotope labeling of their fatty acid-derived lipidome. We show that supplementation of cyanobacterial cultures with deuterated fatty acids can be used to easily detect natural product signatures in individual strains. The utility of this strategy is demonstrated in two cultured cyanobacteria by uncovering analogues of the multidrug-resistance reverting hapalosin, and novel, cytotoxic, lactylate-nocuolin A hybrids – the nocuolactylates.

scholarly journals Out of the abyss: Genome and metagenome mining reveals unexpected environmental distribution of abyssomicins

2019 ◽  
Author(s):  
Alba Iglesias ◽  
Adriel Latorre-Pérez ◽  
James E. M. Stach ◽  
Manuel Porcar ◽  
Javier Pascual
Keyword(s):  
Genome Mining ◽  
Gene Clusters ◽  
Metagenomic Data ◽  
Model Organisms ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Environmental Distribution ◽  
Regulatory Systems ◽  
Terrestrial Habitats ◽  
Metagenome Mining

AbstractNatural products have traditionally been discovered through the screening of culturable microbial isolates from all sort of environments. The sequencing revolution allowed the identification of dozens of biosynthetic gene clusters (BGCs) within single bacterial genomes, either from cultured or uncultured strains. However, we are still far from fully exploiting the microbial reservoir, as most of the species are non-model organisms with complex regulatory systems and yet recalcitrant to be engineered. Today, genomic and metagenomic data produced by laboratories worldwide covering the most different natural and artificial environments on Earth, are an invaluable source of raw information from which natural product biosynthesis can be accessed. In the present work, we describe the environmental distribution and evolution of the abyssomicin BGC through the analysis of publicly available genomic and metagenomic data. Our results demonstrate that the selection of a pathway-specific enzyme to direct the genome mining is an excellent strategy that led to the identification of 74 new Diels-Alderase homologs and unveiled a surprising prevalence of the abyssomicin BGC within terrestrial habitats, mainly soil and plant-associated, where we have identified five complete and 12 partial new abyssomicin BGCs and 23 new potential abyssomicin BGCs. Our results strongly support the potential of genome and metagenome mining as a key preliminary tool to inform bioprospecting strategies aiming at the identification of new bioactive compounds such as -but not restricted to-abyssomicins.

scholarly journals Correlational networking guides the discovery of cryptic proteases for lanthipeptide maturation

2021 ◽  
Author(s):  
Dan Xue ◽  
Ethan A. Older ◽  
Zheng Zhong ◽  
Zhuo Shang ◽  
Nanzhu Chen ◽  
...  
Keyword(s):  
Biological Function ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Class Iii ◽  
Bacterial Genomes ◽  
Biosynthetic Gene Clusters ◽  
Drug Candidates ◽  
New Class ◽  
New Family ◽  
Global Correlation

Proteases required for lanthipeptide maturation are not encoded in many of their respective biosynthetic gene clusters. These cryptic proteases hinder the study and application of lanthipeptides as promising drug candidates. Here, we establish a global correlation network bridging the gap between lanthipeptide precursors and cryptic proteases. Applying our analysis to 161,954 bacterial genomes, we establish 6,041 correlations between precursors and cryptic proteases, with 91 prioritized. We use network predictions and co-expression analysis to reveal a previously missing protease for the maturation of class I lanthipeptide paenilan. We further discover widely distributed bacterial M16B metallopeptidases of previously unclear biological function as a new family of lanthipeptide proteases. We show the involvement of a pair of bifunctional M16B proteases in the production of new class III lanthipeptides with high substrate specificity. Together, these results demonstrate the strength of our correlational networking approach to the discovery of cryptic lanthipeptide proteases.

scholarly journals Phylogenetic analysis of the salinipostin γ-butyrolactone gene cluster uncovers new potential for bacterial signaling-molecule diversity

2020 ◽  
Author(s):  
Kaitlin E. Creamer ◽  
Yuta Kudo ◽  
Bradley S. Moore ◽  
Paul R. Jensen
Keyword(s):  
Gene Cluster ◽  
Species Interactions ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Signaling Molecules ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Specialized Metabolism ◽  
Bacterial Phyla ◽  
Marine Actinomycete

AbstractBacteria communicate by small-molecule chemicals that facilitate intra- and inter-species interactions. These extracellular signaling molecules mediate diverse processes including virulence, bioluminescence, biofilm formation, motility, and specialized metabolism. The signaling molecules produced by members of the phylum Actinobacteria are generally comprised of γ-butyrolactones, γ-butenolides, and furans. The best known actinomycete γ-butyrolactone is A-factor, which triggers specialized metabolism and morphological differentiation in the genus Streptomyces. Salinipostins A-K are unique γ-butyrolactone molecules with rare phosphotriester moieties that were recently characterized from the marine actinomycete genus Salinispora. The production of these compounds has been linked to the 9-gene biosynthetic gene cluster spt. Critical to salinipostin assembly is the γ-butyrolactone synthase encoded by spt9. Here, we report the global distribution of spt9 among sequenced bacterial genomes, revealing a surprising diversity of gene homologs across 12 bacterial phyla, the majority of which are not known to produce γ-butyrolactones. Further analyses uncovered a large group of spt-like gene clusters outside of the genus Salinispora, suggesting the production of new salinipostin-like diversity. These gene clusters show evidence of horizontal transfer between many bacterial taxa and location specific homologous recombination exchange among Salinispora strains. The results suggest that γ-butyrolactone production may be more widespread than previously recognized. The identification of new γ-butyrolactone biosynthetic gene clusters is the first step towards understanding the regulatory roles of the encoded small molecules in Actinobacteria.ImportanceSignaling molecules orchestrate a wide variety of bacterial behaviors. Among Actinobacteria, γ-butyrolactones mediate morphological changes and regulate specialized metabolism. Despite their importance, few γ-butyrolactones have been linked to their cognate biosynthetic gene clusters. A new series of γ-butyrolactones called the salinipostins was recently identified from the marine actinomycete genus Salinispora and linked to the spt biosynthetic gene cluster. Here we report the detection of spt-like gene clusters in diverse bacterial families not known for the production of this class of compounds. This finding expands the taxonomic range of bacteria that may employ this class of compounds and provides opportunities to discover new compounds associated with chemical communication.

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