scholarly journals The Modulation of SCO2730/31 Copper Chaperone/Transporter Orthologue Expression Enhances Secondary Metabolism in Streptomycetes

2021 ◽  
Vol 22 (18) ◽  
pp. 10143
Author(s):  
Nathaly González-Quiñónez ◽  
Ignacio Gutiérrez-Del-Río ◽  
Paula García-Cancela ◽  
Gemma Fernández-García ◽  
Sergio Alonso-Fernández ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Secondary Metabolite ◽  
Streptomyces Coelicolor ◽  
Developmental Cycle ◽  
Copper Chaperone ◽  
Proof Of Concept ◽  
Antisense Mrna ◽  
Complex Development ◽  
P Type

Streptomycetes are important biotechnological bacteria that produce several clinically bioactive compounds. They have a complex development, including hyphae differentiation and sporulation. Cytosolic copper is a well-known modulator of differentiation and secondary metabolism. The interruption of the Streptomyces coelicolor SCO2730 (copper chaperone, SCO2730::Tn5062 mutant) blocks SCO2730 and reduces SCO2731 (P-type ATPase copper export) expressions, decreasing copper export and increasing cytosolic copper. This mutation triggers the expression of 13 secondary metabolite clusters, including cryptic pathways, during the whole developmental cycle, skipping the vegetative, non-productive stage. As a proof of concept, here, we tested whether the knockdown of the SCO2730/31 orthologue expression can enhance secondary metabolism in streptomycetes. We created a SCO2730/31 consensus antisense mRNA from the sequences of seven key streptomycetes, which helped to increase the cytosolic copper in S. coelicolor, albeit to a lower level than in the SCO2730::Tn5062 mutant. This antisense mRNA affected the production of at least six secondary metabolites (CDA, 2-methylisoborneol, undecylprodigiosin, tetrahydroxynaphtalene, α-actinorhodin, ε-actinorhodin) in the S. coelicolor, and five (phenanthroviridin, alkylresorcinol, chloramphenicol, pikromycin, jadomycin G) in the S. venezuelae; it also helped to alter the S. albus metabolome. The SCO2730/31 consensus antisense mRNA designed here constitutes a tool for the knockdown of SCO2730/31 expression and for the enhancement of Streptomyces’ secondary metabolism.

scholarly journals Comparative Transcriptome Analysis Shows Conserved Metabolic Regulation during Production of Secondary Metabolites in Filamentous Fungi

mSystems ◽  
2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Jens Christian Nielsen ◽  
Sylvain Prigent ◽  
Sietske Grijseels ◽  
Mhairi Workman ◽  
Boyang Ji ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Secondary Metabolite ◽  
Filamentous Fungi ◽  
Metabolic Regulation ◽  
Fungal Species ◽  
Efficient Production ◽  
Fungal Cell ◽  
Fungal Metabolism ◽  
Cell Factories

ABSTRACTFilamentous fungi possess great potential as sources of medicinal bioactive compounds, such as antibiotics, but efficient production is hampered by a limited understanding of how their metabolism is regulated. We investigated the metabolism of six secondary metabolite-producing fungi of thePenicilliumgenus during nutrient depletion in the stationary phase of batch fermentations and assessed conserved metabolic responses across species using genome-wide transcriptional profiling. A coexpression analysis revealed that expression of biosynthetic genes correlates with expression of genes associated with pathways responsible for the generation of precursor metabolites for secondary metabolism. Our results highlight the main metabolic routes for the supply of precursors for secondary metabolism and suggest that the regulation of fungal metabolism is tailored to meet the demands for secondary metabolite production. These findings can aid in identifying fungal species that are optimized for the production of specific secondary metabolites and in designing metabolic engineering strategies to develop high-yielding fungal cell factories for production of secondary metabolites.IMPORTANCESecondary metabolites are a major source of pharmaceuticals, especially antibiotics. However, the development of efficient processes of production of secondary metabolites has proved troublesome due to a limited understanding of the metabolic regulations governing secondary metabolism. By analyzing the conservation in gene expression across secondary metabolite-producing fungal species, we identified a metabolic signature that links primary and secondary metabolism and that demonstrates that fungal metabolism is tailored for the efficient production of secondary metabolites. The insight that we provide can be used to develop high-yielding fungal cell factories that are optimized for the production of specific secondary metabolites of pharmaceutical interest.

scholarly journals Variation Among Biosynthetic Gene Clusters, Secondary Metabolite Profiles, and Cards of Virulence Across Aspergillus Species

Genetics ◽  
2020 ◽  
Vol 216 (2) ◽  
pp. 481-497 ◽  
Author(s):  
Jacob L. Steenwyk ◽  
Matthew E. Mead ◽  
Sonja L. Knowles ◽  
Huzefa A. Raja ◽  
Christopher D. Roberts ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Secondary Metabolite ◽  
Immune Cell ◽  
Sequence Divergence ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Host Immune System ◽  
Biosynthetic Gene ◽  
Genetic Determinants

Aspergillus fumigatus is a major human pathogen. In contrast, Aspergillus fischeri and the recently described Aspergillus oerlinghausenensis, the two species most closely related to A. fumigatus, are not known to be pathogenic. Some of the genetic determinants of virulence (or “cards of virulence”) that A. fumigatus possesses are secondary metabolites that impair the host immune system, protect from host immune cell attacks, or acquire key nutrients. To examine whether secondary metabolism-associated cards of virulence vary between these species, we conducted extensive genomic and secondary metabolite profiling analyses of multiple A. fumigatus, one A. oerlinghausenensis, and multiple A. fischeri strains. We identified two cards of virulence (gliotoxin and fumitremorgin) shared by all three species and three cards of virulence (trypacidin, pseurotin, and fumagillin) that are variable. For example, we found that all species and strains examined biosynthesized gliotoxin, which is known to contribute to virulence, consistent with the conservation of the gliotoxin biosynthetic gene cluster (BGC) across genomes. For other secondary metabolites, such as fumitremorgin, a modulator of host biology, we found that all species produced the metabolite but that there was strain heterogeneity in its production within species. Finally, species differed in their biosynthesis of fumagillin and pseurotin, both contributors to host tissue damage during invasive aspergillosis. A. fumigatus biosynthesized fumagillin and pseurotin, while A. oerlinghausenensis biosynthesized fumagillin and A. fischeri biosynthesized neither. These biochemical differences were reflected in sequence divergence of the intertwined fumagillin/pseurotin BGCs across genomes. These results delineate the similarities and differences in secondary metabolism-associated cards of virulence between a major fungal pathogen and its nonpathogenic closest relatives, shedding light onto the genetic and phenotypic changes associated with the evolution of fungal pathogenicity.

From molecular genetics and secondary metabolism to molecular metabolites and secondary genetics

1995 ◽  
Vol 73 (S1) ◽  
pp. 917-924 ◽  
Author(s):  
J. W. Bennett
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Secondary Metabolite ◽  
Fatty Acid Biosynthesis ◽  
Morphological Characters ◽  
Model Systems ◽  
Chain Elongation ◽  
Research Approach ◽  
Active Growth ◽  
Hybrid Molecules

Secondary metabolites constitute a huge array of low molecular weight natural products that cannot be easily defined. Largely produced by bacteria, fungi, and green plants, they tend to be synthesized after active growth has ceased, in families of similar compounds, often at the same time as species-specific morphological characters become apparent. Although, in many cases, the function that the secondary metabolite performs in the producing organism is unknown, the bioactivity of these compounds has been exploited since prehistoric times as drugs, poisons, food flavoring agents, and so forth. In fungi, the polyketide family is the largest known group of secondary metabolite compounds. Polyketides are synthesized from acetate by a mechanism analogous to fatty acid biosynthesis but involving changes in oxidation level and stereochemistry during the chain-elongation process. The fungal polyketide biosynthetic pathways for aflatoxin and patulin have emerged as model systems. The use of blocked mutants has been an essential part of the research approach for both pathways. Molecular methods of studying fungal secondary metabolites were first used with penicillin and cephalosporin, both of which are amino acid derived. Most of the basic molecular work on polyketides was done with streptomycete-derived compounds; however, enough fungal data are now available to compare fungal and streptomycete polyketide synthases, as well as to map the genes involved in a number of polyketide pathways from both groups. The traditional dogma, derived from classical genetics, that genes for fungal pathways are unlinked, has been overturned. In addition, cloning of structural genes facilitates the formation of hybrid molecules, and we are on the brink of understanding certain regulatory functions. Key words: fungal metabolism, secondary metabolism, polyketide, β-lactam, product discovery.

scholarly journals Identification of microRNAs from Medicinal Plant Murraya koenigii by High-Throughput Sequencing and Their Functional Implications in Secondary Metabolite Biosynthesis

Plants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 46
Author(s):  
Claudia Gutiérrez-García ◽  
Shiek S. S. J. Ahmed ◽  
Sathishkumar Ramalingam ◽  
Dhivya Selvaraj ◽  
Aashish Srivastava ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Medicinal Plant ◽  
Secondary Metabolism ◽  
Secondary Metabolite ◽  
High Throughput ◽  
Noncoding Rna ◽  
High Throughput Sequencing ◽  
Mirna Profile ◽  
Murraya Koenigii ◽  
Secondary Metabolite Biosynthesis

MicroRNAs (miRNAs) are small noncoding RNA molecules that play crucial post-transcriptional regulatory roles in plants, including development and stress-response signaling. However, information about their involvement in secondary metabolism is still limited. Murraya koenigii is a popular medicinal plant, better known as curry leaves, that possesses pharmaceutically active secondary metabolites. The present study utilized high-throughput sequencing technology to investigate the miRNA profile of M. koenigii and their association with secondary metabolite biosynthesis. A total of 343,505 unique reads with lengths ranging from 16 to 40 nt were obtained from the sequencing data, among which 142 miRNAs were identified as conserved and 7 as novel miRNAs. Moreover, 6078 corresponding potential target genes of M. koenigii miRNAs were recognized in this study. Interestingly, several conserved and novel miRNAs of M. koenigii were found to target key enzymes of the terpenoid backbone and the flavonoid biosynthesis pathways. Furthermore, to validate the sequencing results, the relative expression of eight randomly selected miRNAs was determined by qPCR. To the best of our knowledge, this is the first report of the M. koenigii miRNA profile that may provide useful information for further elucidation of the involvement of miRNAs in secondary metabolism. These findings might be crucial in the future to generate artificial-miRNA-based, genetically engineered M. koenigii plants for the overproduction of medicinally highly valuable secondary metabolites.

Effect of Butyrolactone I on the Producing Fungus,Aspergillus terreus

1998 ◽  
Vol 64 (10) ◽  
pp. 3707-3712 ◽  
Author(s):  
Timothy G. Schimmel ◽  
Allen D. Coffman ◽  
Sarah J. Parsons
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Secondary Metabolite ◽  
Aspergillus Terreus ◽  
Hyphal Growth ◽  
Secondary Metabolite Production ◽  
Growth Unit ◽  
Filamentous Bacteria ◽  
Hyphal Branching ◽  
Metabolite Production

ABSTRACT Butyrolactone I [α-oxo-β-(p-hydroxyphenyl)-γ-(p-hydroxy-m-3,3-dimethylallyl-benzyl)-γ-methoxycarbonyl-γ-butyrolactone] is produced as a secondary metabolite by Aspergillus terreus. Because small butyrolactone-containing molecules act as self-regulating factors in some bacteria, the effects of butyrolactone I on the producing organism were studied; specifically, changes in morphology, sporulation, and secondary metabolism were studied. Threefold or greater increases in hyphal branching (with concomitant decreases in the average hyphal growth unit), submerged sporulation, and secondary metabolism were observed when butyrolactone I was added to cultures of A. terreus. Among the secondary metabolites whose production was increased by this treatment was the therapeutically important compound lovastatin. These findings indicate that butyrolactone I induces morphological and sporulation changes inA. terreus and enhances secondary metabolite production in a manner similar to that previously reported for filamentous bacteria.

scholarly journals Recovering genomic clusters of secondary metabolites from lakes: a Metagenomics 2.0 approach

2017 ◽  
Author(s):  
Rafael R. C. Cuadrat ◽  
Danny Ionescu ◽  
Alberto M. R. Davila ◽  
Hans-Peter Grossart
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolism ◽  
Secondary Metabolite ◽  
Sequence Coverage ◽  
Probabilistic Distances ◽  
Detection Approach ◽  
North Eastern ◽  
Genomic Clusters ◽  
Long Genes

AbstractBackgroundMetagenomic approaches became increasingly popular in the past decades due to decreasing costs of DNA sequencing and bioinformatics development. So far, however, the recovery of long genes coding for secondary metabolism still represents a big challenge. Often, the quality of metagenome assemblies is poor, especially in environments with a high microbial diversity where sequence coverage is low and complexity of natural communities high. Recently, new and improved algorithms for binning environmental reads and contigs have been developed to overcome such limitations. Some of these algorithms use a similarity detection approach to classify the obtained reads into taxonomical units and to assemble draft genomes. This approach, however, is quite limited since it can classify exclusively sequences similar to those available (and well classified) in the databases.In this work, we used draft genomes from Lake Stechlin, north-eastern Germany, recovered by MetaBat, an efficient binning tool that integrates empirical probabilistic distances of genome abundance, and tetranucleotide frequency for accurate metagenome binning. These genomes were screened for secondary metabolism genes, such as polyketide synthases (PKS) and non-ribosomal peptide synthases (NRPS), using the Anti-SMASH and NAPDOS workflows.ResultsWith this approach we were able to identify 243 secondary metabolite clusters from 121 genomes recovered from the lake samples. A total of 18 NRPS, 19 PKS and 3 hybrid PKS/NRPS clusters were found. In addition, it was possible to predict the partial structure of several secondary metabolite clusters allowing for taxonomical classifications and phylogenetic inferences.ConclusionsOur approach revealed a great potential to recover and study secondary metabolites genes from any aquatic ecosystem.

Genome sequence of Novosphingobium malaysiense strain MUSC 273T, novel alpha-proteobacterium isolated from intertidal soil

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Hooi-Leng Ser ◽  
Wai-Fong Yin ◽  
Kok-Gan Chan ◽  
Nurul-Syakima Ab Mutalib ◽  
Learn-Han Lee
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Genome Sequence ◽  
Catalase Activity ◽  
Gene Clusters ◽  
Rrna Genes ◽  
Gram Negative ◽  
Genomic Features

Novosphingobium malaysiense strain MUSC 273T is a recently identified Gram-negative, aerobic alpha-proteobacterium. The strain was isolated from intertidal soil with strong catalase activity. The genome sequence comprises 5,027,021 bp, with 50 tRNA and 3 rRNA genes. Further analysis identified presence of secondary metabolite gene clusters within genome of MUSC 273T. Knowledge of the genomic features of the strain may allow further biotechnological exploitation, particularly for production of secondary metabolites as well as production of industrially important enzymes

Regio- and stereoselective intermolecular phenol coupling enzymes in secondary metabolite biosynthesis

2021 ◽  
Author(s):  
Wolfgang Hüttel ◽  
Michael Müller
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Metabolic Pathways ◽  
Cyp Enzymes ◽  
Secondary Metabolite Biosynthesis

Phenol coupling enzymes, especially laccases and CYP-enzymes create an enormous diversity of biarylic secondary metabolites in fungi, plants, and bacteria. The enzymes and the elucidation of the corresponding metabolic pathways are presented.

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