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Nature Reviews. Microbiology Mar 2019One of the exciting movements in microbial sciences has been a refocusing and revitalization of efforts to mine the fungal secondary metabolome. The magnitude of... (Review)
Review
One of the exciting movements in microbial sciences has been a refocusing and revitalization of efforts to mine the fungal secondary metabolome. The magnitude of biosynthetic gene clusters (BGCs) in a single filamentous fungal genome combined with the historic number of sequenced genomes suggests that the secondary metabolite wealth of filamentous fungi is largely untapped. Mining algorithms and scalable expression platforms have greatly expanded access to the chemical repertoire of fungal-derived secondary metabolites. In this Review, I discuss new insights into the transcriptional and epigenetic regulation of BGCs and the ecological roles of fungal secondary metabolites in warfare, defence and development. I also explore avenues for the identification of new fungal metabolites and the challenges in harvesting fungal-derived secondary metabolites.
Topics: Drug Discovery; Epigenesis, Genetic; Fungi; Gene Expression Regulation, Fungal; Genome, Fungal; Multigene Family; Secondary Metabolism
PubMed: 30531948
DOI: 10.1038/s41579-018-0121-1 -
Plant Physiology Sep 2020The plant kingdom produces hundreds of thousands of low molecular weight organic compounds. Based on the assumed functions of these compounds, the research community has... (Review)
Review
The plant kingdom produces hundreds of thousands of low molecular weight organic compounds. Based on the assumed functions of these compounds, the research community has classified them into three overarching groups: primary metabolites, which are directly required for plant growth; secondary (or specialized) metabolites, which mediate plant-environment interactions; and hormones, which regulate organismal processes and metabolism. For decades, this functional trichotomy of plant metabolism has shaped theory and experimentation in plant biology. However, exact biochemical boundaries between these different metabolite classes were never fully established. A new wave of genetic and chemical studies now further blurs these boundaries by demonstrating that secondary metabolites are multifunctional; they can function as potent regulators of plant growth and defense as well as primary metabolites sensu lato. Several adaptive scenarios may have favored this functional diversity for secondary metabolites, including signaling robustness and cost-effective storage and recycling. Secondary metabolite multifunctionality can provide new explanations for ontogenetic patterns of defense production and can refine our understanding of plant-herbivore interactions, in particular by accounting for the discovery that adapted herbivores misuse plant secondary metabolites for multiple purposes, some of which mirror their functions in plants. In conclusion, recent work unveils the limits of our current functional classification system for plant metabolites. Viewing secondary metabolites as integrated components of metabolic networks that are dynamically shaped by environmental selection pressures and transcend multiple trophic levels can improve our understanding of plant metabolism and plant-environment interactions.
Topics: Adaptation, Physiological; Plant Development; Plants; Secondary Metabolism
PubMed: 32636341
DOI: 10.1104/pp.20.00433 -
Microbiology Spectrum Nov 2016Many Fungi have a well-developed secondary metabolism. The diversity of fungal species and the diversification of biosynthetic gene clusters underscores a nearly... (Review)
Review
Many Fungi have a well-developed secondary metabolism. The diversity of fungal species and the diversification of biosynthetic gene clusters underscores a nearly limitless potential for metabolic variation and an untapped resource for drug discovery and synthetic biology. Much of the ecological success of the filamentous fungi in colonizing the planet is owed to their ability to deploy their secondary metabolites in concert with their penetrative and absorptive mode of life. Fungal secondary metabolites exhibit biological activities that have been developed into life-saving medicines and agrochemicals. Toxic metabolites, known as mycotoxins, contaminate human and livestock food and indoor environments. Secondary metabolites are determinants of fungal diseases of humans, animals, and plants. Secondary metabolites exhibit a staggering variation in chemical structures and biological activities, yet their biosynthetic pathways share a number of key characteristics. The genes encoding cooperative steps of a biosynthetic pathway tend to be located contiguously on the chromosome in coregulated gene clusters. Advances in genome sequencing, computational tools, and analytical chemistry are enabling the rapid connection of gene clusters with their metabolic products. At least three fungal drug precursors, penicillin K and V, mycophenolic acid, and pleuromutilin, have been produced by synthetic reconstruction and expression of respective gene clusters in heterologous hosts. This review summarizes general aspects of fungal secondary metabolism and recent developments in our understanding of how and why fungi make secondary metabolites, how these molecules are produced, and how their biosynthetic genes are distributed across the Fungi. The breadth of fungal secondary metabolite diversity is highlighted by recent information on the biosynthesis of important fungus-derived metabolites that have contributed to human health and agriculture and that have negatively impacted crops, food distribution, and human environments.
Topics: Biosynthetic Pathways; Diterpenes; Fungi; Genome, Fungal; Humans; Mycophenolic Acid; Mycotoxins; Polycyclic Compounds; Secondary Metabolism; Synthetic Biology; Pleuromutilins
PubMed: 27809954
DOI: 10.1128/microbiolspec.FUNK-0009-2016 -
Molecules (Basel, Switzerland) Mar 2018Plant secondary metabolites (SMs) are not only a useful array of natural products but also an important part of plant defense system against pathogenic attacks and... (Review)
Review
Plant secondary metabolites (SMs) are not only a useful array of natural products but also an important part of plant defense system against pathogenic attacks and environmental stresses. With remarkable biological activities, plant SMs are increasingly used as medicine ingredients and food additives for therapeutic, aromatic and culinary purposes. Various genetic, ontogenic, morphogenetic and environmental factors can influence the biosynthesis and accumulation of SMs. According to the literature reports, for example, SMs accumulation is strongly dependent on a variety of environmental factors such as light, temperature, soil water, soil fertility and salinity, and for most plants, a change in an individual factor may alter the content of SMs even if other factors remain constant. Here, we review with emphasis how each of single factors to affect the accumulation of plant secondary metabolites, and conduct a comparative analysis of relevant natural products in the stressed and unstressed plants. Expectantly, this documentary review will outline a general picture of environmental factors responsible for fluctuation in plant SMs, provide a practical way to obtain consistent quality and high quantity of bioactive compounds in vegetation, and present some suggestions for future research and development.
Topics: Biological Products; Plants; Salinity; Secondary Metabolism; Soil; Stress, Physiological; Temperature; Water
PubMed: 29584636
DOI: 10.3390/molecules23040762 -
Nucleic Acids Research Jul 2021Many microorganisms produce natural products that form the basis of antimicrobials, antivirals, and other drugs. Genome mining is routinely used to complement...
Many microorganisms produce natural products that form the basis of antimicrobials, antivirals, and other drugs. Genome mining is routinely used to complement screening-based workflows to discover novel natural products. Since 2011, the "antibiotics and secondary metabolite analysis shell-antiSMASH" (https://antismash.secondarymetabolites.org/) has supported researchers in their microbial genome mining tasks, both as a free-to-use web server and as a standalone tool under an OSI-approved open-source license. It is currently the most widely used tool for detecting and characterising biosynthetic gene clusters (BGCs) in bacteria and fungi. Here, we present the updated version 6 of antiSMASH. antiSMASH 6 increases the number of supported cluster types from 58 to 71, displays the modular structure of multi-modular BGCs, adds a new BGC comparison algorithm, allows for the integration of results from other prediction tools, and more effectively detects tailoring enzymes in RiPP clusters.
Topics: Bacteria; Biological Products; Biosynthetic Pathways; Fungi; Genome, Microbial; Secondary Metabolism; Software
PubMed: 33978755
DOI: 10.1093/nar/gkab335 -
Nucleic Acids Research Jul 2023Microorganisms produce small bioactive compounds as part of their secondary or specialised metabolism. Often, such metabolites have antimicrobial, anticancer,...
Microorganisms produce small bioactive compounds as part of their secondary or specialised metabolism. Often, such metabolites have antimicrobial, anticancer, antifungal, antiviral or other bio-activities and thus play an important role for applications in medicine and agriculture. In the past decade, genome mining has become a widely-used method to explore, access, and analyse the available biodiversity of these compounds. Since 2011, the 'antibiotics and secondary metabolite analysis shell-antiSMASH' (https://antismash.secondarymetabolites.org/) has supported researchers in their microbial genome mining tasks, both as a free to use web server and as a standalone tool under an OSI-approved open source licence. It is currently the most widely used tool for detecting and characterising biosynthetic gene clusters (BGCs) in archaea, bacteria, and fungi. Here, we present the updated version 7 of antiSMASH. antiSMASH 7 increases the number of supported cluster types from 71 to 81, as well as containing improvements in the areas of chemical structure prediction, enzymatic assembly-line visualisation and gene cluster regulation.
Topics: Software; Computers; Bacteria; Archaea; Genome, Microbial; Multigene Family; Secondary Metabolism
PubMed: 37140036
DOI: 10.1093/nar/gkad344 -
ELife Nov 2022Microbes have disproportionate impacts on the macroscopic world. This is in part due to their ability to grow to large populations that collectively secrete massive...
Microbes have disproportionate impacts on the macroscopic world. This is in part due to their ability to grow to large populations that collectively secrete massive amounts of secondary metabolites and alter their environment. Yet, the conditions favoring secondary metabolism despite the potential costs for primary metabolism remain unclear. Here we investigated the biosurfactants that the bacterium makes and secretes to decrease the surface tension of surrounding liquid. Using a combination of genomics, metabolomics, transcriptomics, and mathematical modeling we show that the ability to make surfactants from glycerol varies inconsistently across the phylogenetic tree; instead, lineages that lost this ability are also worse at reducing the oxidative stress of primary metabolism on glycerol. Experiments with different carbon sources support a link with oxidative stress that explains the inconsistent distribution across the phylogeny and suggests a general principle: lineages produce surfactants if they can reduce the oxidative stress produced by primary metabolism and have excess resources, beyond their primary needs, to afford secondary metabolism. These results add a new layer to the regulation of a secondary metabolite unessential for primary metabolism but important to change physical properties of the environments surrounding bacterial populations.
Topics: Secondary Metabolism; Glycerol; Phylogeny; Biological Transport; Carbon; Pseudomonas aeruginosa
PubMed: 36409069
DOI: 10.7554/eLife.76119 -
Plant Signaling & Behavior Jul 2021Plant growth and development is dependent on the regulation of classes of microRNAs (miRNAs) that have emerged as important gene regulators. These miRNAs can regulate... (Review)
Review
Plant growth and development is dependent on the regulation of classes of microRNAs (miRNAs) that have emerged as important gene regulators. These miRNAs can regulate plant gene expression to function. They play an important roles in biological homeostasis and environmental response controls. A wide range of plant biological and metabolic processes, including developmental timing, tissues specific development, and differentiation, depends on miRNAs. They perpetually regulate secondary metabolite functions in different plant family lines. Mapping of molecular phylogenies shows the distribution of secondary metabolism in the plant territory. More importantly, a lot of information related to miRNA regulatory processes in plants is revealed, but the role of miRNAs in secondary metabolism regulation and functions of the metabolites are still unclear. In this review, we pinnacle some potential miRNAs regulating the secondary metabolite biosynthesis activities in plants. This will provide an alternative knowledge for functional studies of secondary metabolism.
Topics: MicroRNAs; Plants; RNA, Plant; Secondary Metabolism
PubMed: 33938393
DOI: 10.1080/15592324.2021.1915590 -
Cells Dec 2022In filamentous fungal species, growth, development, and secondary metabolism are genetically programmed biological processes, which require precise coordination of... (Review)
Review
In filamentous fungal species, growth, development, and secondary metabolism are genetically programmed biological processes, which require precise coordination of diverse signaling elements, transcription factors (TFs), upstream and downstream regulators, and biosynthetic genes. For the last few decades, regulatory roles of these controllers in asexual/sexual development and primary/secondary metabolism of species have been extensively studied. Among a wide spectrum of regulators, a handful of global regulators govern upstream regulation of development and metabolism by directly and/or indirectly affecting the expression of various genes including TFs. In this review, with the model fungus as the central figure, we summarize the most well-studied main upstream regulators and their regulatory roles. Specifically, we present key functions of heterotrimeric G proteins and G protein-coupled receptors in signal transduction), the family proteins governing development and metabolism, LaeA as a global regulator of secondary metabolism, and NsdD, a key GATA-type TF, affecting development and secondary metabolism and provide a snapshot of overall upstream regulatory processes underlying growth, development, and metabolism in fungi.
Topics: Fungal Proteins; Secondary Metabolism; Aspergillus nidulans; Transcription Factors; Signal Transduction
PubMed: 36611796
DOI: 10.3390/cells12010002 -
Marine Drugs Jan 2021Marine invertebrates are promising sources of novel bioactive secondary metabolites, and organisms like sponges, ascidians and nudibranchs are characterised by... (Review)
Review
Marine invertebrates are promising sources of novel bioactive secondary metabolites, and organisms like sponges, ascidians and nudibranchs are characterised by possessing potent defensive chemicals. Animals that possess chemical defences often advertise this fact with aposematic colouration that potential predators learn to avoid. One seemingly defenceless group that can present bright colouration patterns are flatworms of the order Polycladida. Although members of this group have typically been overlooked due to their solitary and benthic nature, recent studies have isolated the neurotoxin tetrodotoxin from these mesopredators. This review considers the potential of polyclads as potential sources of natural products and reviews what is known of the activity of the molecules found in these animals. Considering the ecology and diversity of polyclads, only a small number of species from both suborders of Polycladida, Acotylea and Cotylea have been investigated for natural products. As such, confirming assumptions as to which species are in any sense toxic or if the compounds they use are biosynthesised, accumulated from food or the product of symbiotic bacteria is difficult. However, further research into the group is suggested as these animals often display aposematic colouration and are known to prey on invertebrates rich in bioactive secondary metabolites.
Topics: Animals; Biological Products; Platyhelminths; Protein Structure, Secondary; Protein Structure, Tertiary; Secondary Metabolism
PubMed: 33494164
DOI: 10.3390/md19020047