Fungal Dihydroxynaphthalene-Melanin: Diversity-Oriented Biosynthesis through Enzymatic and Non-enzymatic Transformations

Synlett ◽  
2017 ◽  
Vol 28 (18) ◽  
pp. 2360-2372 ◽  
Author(s):  
Michael Müller ◽  
Syed Husain
Keyword(s):  
Biosynthetic Pathway ◽  
Molecular Diversity ◽  
Magnaporthe Grisea ◽  
Gene Clusters ◽  
Extended Model ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Melanin Biosynthesis ◽  
Aromatic Polyketides

Tetrahydroxynaphthalene reductase (T4HNR) from Magnaporthe grisea catalyzes the reduction of polyhydroxynaphthalenes, hydroxynaphthoquinones, and 1,4-diketones, with extensive ramifications for the biosynthesis of (shunt) metabolites related to 1,8-dihydroxynaphthalene (DHN)-melanin biosynthesis. Hence, an extended model for DHN-melanin biosynthesis has been developed which is based on a screening hypothesis involving non-enzymatic transformations such as oxidations and tautomerism. This has led to the broadening of the functions of several short-chain dehydrogenases/reductases (SDRs) capable of reducing polyhydroxyanthracenes, polyhydroxynaphthalenes, and polyhydroxybenzenes. Our work, broadening the scope of enzymatic dearomatization reactions, provides access to the biocatalytic synthesis of a variety of natural and natural-like products. Furthermore, the results described in this account provide the basis for the identification of other SDRs amenable to reducing aromatic compounds, and thus enable the identification of biosynthetic gene clusters most likely involved in the biosynthesis of aromatic polyketides.1 Introduction2 Biosynthesis of 1,8-Dihydroxynaphthalene (DHN)3 Biosynthesis of Shunt Metabolites and the Origin of Molecular Diversity3.1 Role of Spontaneous Non-enzymatic Oxidations3.2 Role of T4HNR and T3HNR3.3 Role of Tautomerism in the Biosynthesis of (Shunt) Metabolites4 Extended Melanin Biosynthesis: A Screening Hypothesis5 Useful Outcomes of the Newly Identified Melanin Biosynthetic Pathway5.1 NADP+ Regeneration Using Lawsone as Mediator5.2 Anthrahydroquinone as an Intermediate in the Biosynthesis of Chrysophanol and Other Anthraquinone-Derived Products5.3 Combination of T3HNR and GDH To Access trans-Ketodiols5.4 Phloroglucinol Reductases (PGRs) To Dearomatize Monomeric Phenols6 Conclusion

scholarly journals Identification and distribution of gene clusters required for synthesis of sphingolipid metabolism inhibitors in diverse species of the filamentous fungus Fusarium

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Hye-Seon Kim ◽  
Jessica M. Lohmar ◽  
Mark Busman ◽  
Daren W. Brown ◽  
Todd A. Naumann ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Sphingolipid Metabolism ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Dehydrogenase Gene ◽  
Food And Feed ◽  
Feed Safety

Abstract Background Sphingolipids are structural components and signaling molecules in eukaryotic membranes, and many organisms produce compounds that inhibit sphingolipid metabolism. Some of the inhibitors are structurally similar to the sphingolipid biosynthetic intermediate sphinganine and are referred to as sphinganine-analog metabolites (SAMs). The mycotoxins fumonisins, which are frequent contaminants in maize, are one family of SAMs. Due to food and feed safety concerns, fumonisin biosynthesis has been investigated extensively, including characterization of the fumonisin biosynthetic gene cluster in the agriculturally important fungi Aspergillus and Fusarium. Production of several other SAMs has also been reported in fungi, but there is almost no information on their biosynthesis. There is also little information on how widely SAM production occurs in fungi or on the extent of structural variation of fungal SAMs. Results Using fumonisin biosynthesis as a model, we predicted that SAM biosynthetic gene clusters in fungi should include a polyketide synthase (PKS), an aminotransferase and a dehydrogenase gene. Surveys of genome sequences identified five putative clusters with this three-gene combination in 92 of 186 Fusarium species examined. Collectively, the putative SAM clusters were distributed widely but discontinuously among the species. We propose that the SAM5 cluster confers production of a previously reported Fusarium SAM, 2-amino-14,16-dimethyloctadecan-3-ol (AOD), based on the occurrence of AOD production only in species with the cluster and on deletion analysis of the SAM5 cluster PKS gene. We also identified SAM clusters in 24 species of other fungal genera, and propose that one of the clusters confers production of sphingofungin, a previously reported Aspergillus SAM. Conclusion Our results provide a genomics approach to identify novel SAM biosynthetic gene clusters in fungi, which should in turn contribute to identification of novel SAMs with applications in medicine and other fields. Information about novel SAMs could also provide insights into the role of SAMs in the ecology of fungi. Such insights have potential to contribute to strategies to reduce fumonisin contamination in crops and to control crop diseases caused by SAM-producing fungi.

scholarly journals Understanding Thioamitide Biosynthesis Using Pathway Engineering and Untargeted Metabolomics

2020 ◽  
Author(s):  
Tom H. Eyles ◽  
Natalia M. Vior ◽  
Rodney Lacret ◽  
Andrew W. Truman
Keyword(s):  
Biosynthetic Pathway ◽  
Gene Clusters ◽  
Untargeted Metabolomics ◽  
Pathway Engineering ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Heterologous Host ◽  
Detailed Understanding ◽  
Precursor Peptide ◽  
Modified Peptides

ABSTRACTThiostreptamide S4 is a thioamitide, a family of promising antitumour ribosomally synthesised and post-translationally modified peptides (RiPPs). The thioamitides are one of the most structurally complex RiPP families, yet very few thioamitide biosynthetic steps have been elucidated, even though the gene clusters of multiple thioamitides have been identified. We hypothesised that engineering the thiostreptamide S4 gene cluster in a heterologous host could provide insights into its biosynthesis when coupled with untargeted metabolomics and targeted mutations of the precursor peptide. Modified gene clusters were constructed, and in-depth metabolomics enabled a detailed understanding of the biosynthetic pathway, including the identification of an effector-like protein critical for amino acid dehydration. We use this biosynthetic understanding to bioinformatically identify new widespread families of RiPP biosynthetic gene clusters, paving the way for future RiPP discovery and engineering.

scholarly journals Activation and Identification of a Griseusin Cluster in Streptomyces sp. CA-256286 by Employing Transcriptional Regulators and Multi-Omics Methods

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6580
Author(s):  
Charlotte Beck ◽  
Tetiana Gren ◽  
Francisco Javier Ortiz-López ◽  
Tue Sparholt Jørgensen ◽  
Daniel Carretero-Molina ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Genome Mining ◽  
Gene Clusters ◽  
Transcriptional Regulators ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Heterologous Host ◽  
Streptomyces Sp ◽  
Identification And Characterization

Streptomyces are well-known producers of a range of different secondary metabolites, including antibiotics and other bioactive compounds. Recently, it has been demonstrated that “silent” biosynthetic gene clusters (BGCs) can be activated by heterologously expressing transcriptional regulators from other BGCs. Here, we have activated a silent BGC in Streptomyces sp. CA-256286 by overexpression of a set of SARP family transcriptional regulators. The structure of the produced compound was elucidated by NMR and found to be an N-acetyl cysteine adduct of the pyranonaphtoquinone polyketide 3′-O-α-d-forosaminyl-(+)-griseusin A. Employing a combination of multi-omics and metabolic engineering techniques, we identified the responsible BGC. These methods include genome mining, proteomics and transcriptomics analyses, in combination with CRISPR induced gene inactivations and expression of the BGC in a heterologous host strain. This work demonstrates an easy-to-implement workflow of how silent BGCs can be activated, followed by the identification and characterization of the produced compound, the responsible BGC, and hints of its biosynthetic pathway.

scholarly journals Bagremycin Antibiotics and Ferroverdin iron-chelators are synthetized by the Same Gene Cluster

2019 ◽  
Author(s):  
Loïc Martinet ◽  
Aymeric Naômé ◽  
Benoit Deflandre ◽  
Marta Maciejewska ◽  
Déborah Tellatin ◽  
...  
Keyword(s):  
Environmental Conditions ◽  
Biosynthetic Pathway ◽  
Gene Clusters ◽  
Iron Chelators ◽  
Hydroxybenzoic Acid ◽  
Iron Availability ◽  
Biosynthetic Gene ◽  
Single Family ◽  
Biosynthetic Gene Clusters ◽  
Specialized Metabolites

AbstractBiosynthetic gene clusters (BGCs) are organized groups of genes involved in the production of specialized metabolites. Typically, one BGC is responsible for the production of one or several similar compounds with bioactivities that usually only vary in terms of strength and/or specificity. Here we show that the previously described ferroverdins and bagremycins, which are families of metabolites with different bioactivities, are produced from the same BGC, whereby the fate of the biosynthetic pathway depends on iron availability. Under conditions of iron depletion, the monomeric bagremycins are formed, which are amino-aromatic antibiotics resulting from the condensation of 3-amino-4-hydroxybenzoic acid with p-vinylphenol. Conversely, when iron is abundantly available, the biosynthetic pathway additionally produces a molecule based on p-vinylphenyl-3-nitroso-4-hydroxybenzoate, which complexes iron to form the trimeric ferroverdins that have anticholesterol activity. Thus our work challenges the concept that BGCs should produce a single family of molecules with one type of bioactivity, the occurrence of the different metabolites being triggered by the environmental conditions.

scholarly journals A Single Biosynthetic Gene Cluster Is Responsible for the Production of Bagremycin Antibiotics and Ferroverdin Iron Chelators

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Loïc Martinet ◽  
Aymeric Naômé ◽  
Benoit Deflandre ◽  
Marta Maciejewska ◽  
Déborah Tellatin ◽  
...  
Keyword(s):  
Natural Product ◽  
Gene Cluster ◽  
Biosynthetic Pathway ◽  
Genome Mining ◽  
Gene Clusters ◽  
Bioactive Molecules ◽  
Bioactive Metabolites ◽  
Biosynthetic Gene ◽  
Single Family ◽  
Biosynthetic Gene Clusters

ABSTRACT Biosynthetic gene clusters (BGCs) are organized groups of genes involved in the production of specialized metabolites. Typically, one BGC is responsible for the production of one or several similar compounds with bioactivities that usually only vary in terms of strength and/or specificity. Here we show that the previously described ferroverdins and bagremycins, which are families of metabolites with different bioactivities, are produced from the same BGC, whereby the fate of the biosynthetic pathway depends on iron availability. Under conditions of iron depletion, the monomeric bagremycins are formed, representing amino-aromatic antibiotics resulting from the condensation of 3-amino-4-hydroxybenzoic acid with p-vinylphenol. Conversely, when iron is abundantly available, the biosynthetic pathway additionally produces a molecule based on p-vinylphenyl-3-nitroso-4-hydroxybenzoate, which complexes iron to form the trimeric ferroverdins that have anticholesterol activity. Thus, our work shows a unique exception to the concept that BGCs should only produce a single family of molecules with one type of bioactivity and that in fact different bioactive molecules may be produced depending on the environmental conditions. IMPORTANCE Access to whole-genome sequences has exposed the general incidence of the so-called cryptic biosynthetic gene clusters (BGCs), thereby renewing their interest for natural product discovery. As a consequence, genome mining is the often first approach implemented to assess the potential of a microorganism for producing novel bioactive metabolites. By revealing a new level of complexity of natural product biosynthesis, we further illustrate the difficulty of estimation of the panel of molecules associated with a BGC based on genomic information alone. Indeed, we found that the same gene cluster is responsible for the production of compounds which differ in terms of structure and bioactivity. The production of these different compounds responds to different environmental triggers, which suggests that multiplication of culture conditions is essential for revealing the entire panel of molecules made by a single BGC.

scholarly journals Influence of Amino Acid Feeding on Production of Calcimycin and Analogs in Streptomyces chartreusis

2021 ◽  
Vol 18 (16) ◽  
pp. 8740
Author(s):  
Kirstin I. Arend ◽  
Julia E. Bandow
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Nitrogen Sources ◽  
Gene Clusters ◽  
Biosynthetic Gene Cluster ◽  
Defined Medium ◽  
Glutamine Supplementation ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters

Streptomyces chartreusis NRRL 3882 produces the polyether ionophore calcimycin and a variety of analogs, which originate from the same biosynthetic gene cluster. The role of calcimycin and its analogs for the producer is unknown, but calcimycin has strong antibacterial activity. Feeding experiments were performed in chemically defined medium systematically supplemented with proteinogenic amino acids to analyze their individual effects on calcimycin synthesis. In the culture supernatants, in addition to known calcimycin analogs, eight so far unknown analogs were detected using LC-MS/MS. Under most conditions cezomycin was the compound produced in highest amounts. The highest production of calcimycin was detected upon feeding with glutamine. Supplementation of the medium with glutamic acid resulted in a decrease in calcimycin production, and supplementation of other amino acids such as tryptophan, lysine, and valine resulted in the decrease in the synthesis of calcimycin and of the known intermediates of the biosynthetic pathway. We demonstrated that the production of calcimycin and its analogs is strongly dependent on amino acid supply. Utilization of amino acids as precursors and as nitrogen sources seem to critically influence calcimycin synthesis. Even amino acids not serving as direct precursors resulted in a different product profile regarding the stoichiometry of calcimycin analogs. Only slight changes in cultivation conditions can lead to major changes in the metabolic output, which highlights the hidden potential of biosynthetic gene clusters. We emphasize the need to further study the extent of this potential to understand the ecological role of metabolite diversity originating from single biosynthetic gene clusters.

scholarly journals Phages weaponize their bacteria with biosynthetic gene clusters

2020 ◽  
Author(s):  
Anna Dragoš ◽  
Aaron J.C. Andersen ◽  
Carlos N. Lozano-Andrade ◽  
Paul J. Kempen ◽  
Ákos T. Kovács ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Specialized Metabolites ◽  
Fitness Advantage ◽  
Large Step ◽  
Bioactive Potential ◽  
Close Relatives

ABSTRACTBacteria produce many different specialized metabolites, which are encoded by biosynthetic gene clusters (BGCs). Despite high industrial relevance owing to broad bioactive potential of these metabolites, their ecological roles remain largely unexplored. We analyze all available genomes for BGCs of phage origin. The BGCs predominantly reside within temperate phages infecting certain commensal and pathogenic bacteria. Nearly all phage BGCs encode bacteriocins, which appear to serve as a strong proxy for phage specificity. Using the gut-associated bacterium Bacillus subtilis, we demonstrate how a temperate phage equips its host with a functional BGC, providing it with a competitive fitness advantage over close relatives. Therefore, certain temperate phages use BGCs to weaponize their bacteria against close relatives, leading to evolutionary benefits from lysogeny to the infected host, and hence, to the phage itself. Our study is a large step towards understanding the natural role of specialized metabolites, as well as mutualistic phage-host relationships.

Genetic dereplication driven discovery of a tricinoloniol acid biosynthetic pathway in Trichoderma hypoxylon

2020 ◽  
Vol 18 (28) ◽  
pp. 5344-5348 ◽  
Author(s):  
Huan Liu ◽  
Yu-Han Pu ◽  
Jin-Wei Ren ◽  
Er-Wei Li ◽  
Li-Xia Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Biosynthetic Pathway ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Targeted Deletion ◽  
Terpene Cyclase

Three new sesquiterpene tricinoloniol acids were found by a genetic dereplication approach in combination with coordinated gene expression of biosynthetic gene clusters of tri and tra. The biosynthetic pathway was identified by targeted deletion of terpene cyclase traA.

scholarly journals Dual Role of GdmH in Producer Immunity and Secretion of the Staphylococcal Lantibiotics Gallidermin and Epidermin

2001 ◽  
Vol 67 (3) ◽  
pp. 1380-1383 ◽  
Author(s):  
Matthias Hille ◽  
Stefanie Kies ◽  
Friedrich Götz ◽  
Andreas Peschel
Keyword(s):  
Antimicrobial Peptides ◽  
Gene Clusters ◽  
Synergistic Activity ◽  
Biosynthetic Gene ◽  
Cellular Functions ◽  
Biosynthetic Gene Clusters ◽  
Atp Binding Cassette Transporters ◽  
Immunity Genes ◽  
Unique Genes

ABSTRACT The biosynthetic gene clusters of the staphylococcal lantibiotics epidermin and gallidermin are distinguished by the presence of the unique genes epiH and gdmH, respectively. They encode accessory factors for the ATP-binding cassette transporters that mediate secretion of the antimicrobial peptides. Here, we show thatgdmH also contributes to immunity to gallidermin but not to nisin. gdmH alone affected susceptibility to gallidermin only moderately, but it led to a multiplication of the immunity level mediated by the FEG immunity genes when cloned together with the gdmT gene, suggesting a synergistic activity of the H and FEG systems. gdmH-related genes were identified in the genomes of several bacteria, indicating an involvement in further cellular functions.

scholarly journals Heterologous Expression of the Oxytetracycline Biosynthetic Pathway in Myxococcus xanthus

2010 ◽  
Vol 76 (8) ◽  
pp. 2681-2683 ◽  
Author(s):  
D. Cole Stevens ◽  
Michael R. Henry ◽  
Kimberly A. Murphy ◽  
Christopher N. Boddy
Keyword(s):  
Drug Discovery ◽  
Heterologous Expression ◽  
Biosynthetic Pathway ◽  
Myxococcus Xanthus ◽  
Gene Clusters ◽  
Biosynthetic Pathways ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Metagenomic Dna ◽  
Dna Libraries

ABSTRACT New natural products for drug discovery may be accessed by heterologous expression of bacterial biosynthetic pathways in metagenomic DNA libraries. However, a “universal” host is needed for this experiment. Herein, we show that Myxococcus xanthus is a potential “universal” host for heterologous expression of polyketide biosynthetic gene clusters.

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