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Ergot Alkaloids: Chemistry, Biology and Toxicology
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Ergot Alkaloids: Chemistry, Biology and Toxicology

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Mycotoxins".

Deadline for manuscript submissions: closed (15 January 2015) | Viewed by 114758

Special Issue Editor

Prof. Dr. Christopher L. Schardl

E-Mail Website
Guest Editor
Department of Plant Pathology, University of Kentucky 201C Plant Science Building, Lexington, KY 40546-0312, USA
Interests: natural products biochemistry, genomics, mycology, plant-fungus symbiosis

Special Issue Information

Dear Colleagues,

Alkaloids encompass a wide diversity of nitrogen-containing specialized (secondary) metabolites, which are often associated with plants and provide defense against herbivores, pathogens and parasites. A class of alkaloids of particular relevance to human society, medicine and agriculture is the ergot alkaloids, so named because many ergot fungi (Claviceps species) produce these metabolites in abundance. Ergot alkaloids are known from plant-symbiotic and plant-pathogenic fungi in family Clavicipitaceae (phylum Ascomycota), from other orders of fungi, and from other biological sources. They range in size and complexity from the tricyclic and tetracyclic clavines to the hexacyclic and heptacyclic ergopeptines. Though some are cytotoxic and antimicrobial, most are primarily neurotropic. Ergot alkaloids can occur in grains contaminated by sclerotia (ergots) of Claviceps species, or in forage grasses, and morning glory plants where they are produced by endophytic fungi. Ingestion of ergot alkaloids causes poisonings described as convulsive or gangrenous ergotism depending on the forms of the alkaloids. On the other hand, at appropriate doses, and sometimes in modified forms, ergot alkaloids are useful as pharmaceuticals, including ergonovine (= ergometrine) in childbirth, ergotamine for migraines, and bromocryptine for Parkinson’s disease. The serendipitous discovery of a particularly hallucinogenic derivative, lysergic acid diethylamide (LSD), played a major role in the Western counterculture of the 1960s and 1970s. The ergot alkaloid biosynthetic pathway, the enzymes involved, and the genes encoding those enzymes have largely been elucidated. Evolutionary diversification of ergot alkaloids stems from changes in substrate and product specificity of some key enzymes, as well as acquisition and losses of genes for biosynthesis and modification enzymes. Fungi with functional ergot alkaloid pathways can have as few as four genes for chanoclavine biosynthesis, or as many as 14 genes for production of an array of lysergic acid amides and ergopeptines. This special issue will address the following aspects of ergot alkaloids:

1. Biosynthetic pathways: Clavines
2: Biosynthetic pathways: Lysergic acid amides and ergopeptines
3. Chemical diversity: Enzyme specificities
4. Chemical diversity: Genetics, genomics and evolution
5. Activities and effects: Humans and small animals
6. Activities and effects: Livestock

Prof. Dr. Christopher L. Schardl
Guest Editor

Keywords

  • ergot alkaloids
  • mycotoxins
  • natural products
  • secondary metabolism
  • biosynthetic pathways
  • enzymes
  • genomics
  • fungi
  • symbiosis
  • toxicology
  • food safety
  • livestock health
  • pasture management
  • forage plants
  • poisonous plants
  • therapeutic drugs
  • pharmacology

Published Papers (11 papers)

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Editorial

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371 KiB  
Editorial
Introduction to the Toxins Special Issue on Ergot Alkaloids
by Christopher L. Schardl
Toxins 2015, 7(10), 4232-4237; https://doi.org/10.3390/toxins7104232 - 20 Oct 2015
Cited by 18 | Viewed by 5640
Abstract
Ergot alkaloids are among the most relevant natural products in the history of toxins and pharmaceuticals. Until the late 20th century, human and livestock exposure to ergot alkaloids was primarily through ingestion of “ergots,” which are spur-shaped or seed-like resting structures (sclerotia) of [...] Read more.
Ergot alkaloids are among the most relevant natural products in the history of toxins and pharmaceuticals. Until the late 20th century, human and livestock exposure to ergot alkaloids was primarily through ingestion of “ergots,” which are spur-shaped or seed-like resting structures (sclerotia) of ergot fungi, the Claviceps species. Because ergots have similar density to grains, traditional threshing techniques generally failed to remove them, and outbreaks of ergot typically led to mass poisonings. [...] Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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Research

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435 KiB  
Article
Ergot Alkaloids in Feed for Pekin Ducks: Toxic Effects, Metabolism and Carry Over into Edible Tissues
by Sven Dänicke
Toxins 2015, 7(6), 2006-2023; https://doi.org/10.3390/toxins7062006 - 02 Jun 2015
Cited by 15 | Viewed by 5635
Abstract
Hardened sclerotia (ergots) of Claviceps purpurea contaminate cereal grains and contain toxic ergot alkaloids (EA). Information on EA toxicity in ducks is scarce. Therefore, the aim of the growth experiment (Day 0–49, n = 54/group) was to titrate the lowest observed adverse effect [...] Read more.
Hardened sclerotia (ergots) of Claviceps purpurea contaminate cereal grains and contain toxic ergot alkaloids (EA). Information on EA toxicity in ducks is scarce. Therefore, the aim of the growth experiment (Day 0–49, n = 54/group) was to titrate the lowest observed adverse effect level (LOAEL) for total ergot alkaloids (TEA). A control diet was prepared without ergots, and the diets designated Ergot 1 to 4 contained 1, 10, 15 and 20 g ergot per kg diet, respectively, corresponding to TEA contents of 0.0, 0.6, 7.0, 11.4 and 16.4 mg/kg. Sensitivity of ducks to EA was most pronounced at the beginning of the experiment when feed intake decreased significantly by 9%, 28%, 41% and 47% in groups Ergot 1 to 4, respectively, compared to the control group. The experiment was terminated after two weeks for ducks exposed to Ergot 3 and 4 due to significant growth retardation. Ergot alkaloid residues in edible tissues were lower than 5 ng/g. Bile was tested positive for ergonovine (=ergometrine = ergobasine) with a mean concentration of 40 ng/g. Overall, the LOAEL amounted to 0.6 mg TA/kg diet suggesting that ducks are not protected by current European Union legislation (1 g ergot/kg unground cereal grains). Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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2068 KiB  
Article
Links between Genetic Groups, Indole Alkaloid Profiles and Ecology within the Grass-Parasitic Claviceps purpurea Species Complex
by Mariell Negård, Silvio Uhlig, Håvard Kauserud, Tom Andersen, Klaus Høiland and Trude Vrålstad
Toxins 2015, 7(5), 1431-1456; https://doi.org/10.3390/toxins7051431 - 28 Apr 2015
Cited by 31 | Viewed by 7613
Abstract
The grass parasitic fungus Claviceps purpurea sensu lato produces sclerotia with toxic indole alkaloids. It constitutes several genetic groups with divergent habitat preferences that recently were delimited into separate proposed species. We aimed to 1) analyze genetic variation of C. purpurea sensu lato [...] Read more.
The grass parasitic fungus Claviceps purpurea sensu lato produces sclerotia with toxic indole alkaloids. It constitutes several genetic groups with divergent habitat preferences that recently were delimited into separate proposed species. We aimed to 1) analyze genetic variation of C. purpurea sensu lato in Norway, 2) characterize the associated indole alkaloid profiles, and 3) explore relationships between genetics, alkaloid chemistry and ecology. Approximately 600 sclerotia from 14 different grass species were subjected to various analyses including DNA sequencing and HPLC-MS. Molecular results, supported by chemical and ecological data, revealed one new genetic group (G4) in addition to two of the three known; G1 (C. purpurea sensu stricto) and G2 (C. humidiphila). G3 (C. spartinae) was not found. G4, which was apparently con-specific with the recently described C. arundinis sp. nov, was predominantly found in very wet habitats on Molinia caerulea and infrequently in saline habitats on Leymus arenarius. Its indole-diterpene profile resembled G2, while its ergot alkaloid profile differed from G2 in high amounts of ergosedmam. In contrast to G1, indole-diterpenes were consistently present in G2 and G4. Our study supports and complements the newly proposed species delimitation of the C. purpurea complex, but challenges some species characteristics including host spectrum, habitat preferences and sclerotial floating ability. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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2258 KiB  
Article
The Key Role of Peltate Glandular Trichomes in Symbiota Comprising Clavicipitaceous Fungi of the Genus Periglandula and Their Host Plants
by Ulrike Steiner, Sabine Hellwig née Kucht, Mahalia A. Ahimsa-Müller, Nicola Grundmann, Shu-Ming Li, Christel Drewke and Eckhard Leistner
Toxins 2015, 7(4), 1355-1373; https://doi.org/10.3390/toxins7041355 - 16 Apr 2015
Cited by 11 | Viewed by 7841
Abstract
Clavicipitaceous fungi producing ergot alkaloids were recently discovered to be epibiotically associated with peltate glandular trichomes of Ipomoea asarifolia and Turbina corymbosa, dicotyledonous plants of the family Convolvulaceae. Mediators of the close association between fungi and trichomes may be sesquiterpenes, main components [...] Read more.
Clavicipitaceous fungi producing ergot alkaloids were recently discovered to be epibiotically associated with peltate glandular trichomes of Ipomoea asarifolia and Turbina corymbosa, dicotyledonous plants of the family Convolvulaceae. Mediators of the close association between fungi and trichomes may be sesquiterpenes, main components in the volatile oil of different convolvulaceous plants. Molecular biological studies and microscopic investigations led to the observation that the trichomes do not only secrete sesquiterpenes and palmitic acid but also seem to absorb ergot alkaloids from the epibiotic fungal species of the genus Periglandula. Thus, the trichomes are likely to have a dual and key function in a metabolic dialogue between fungus and host plant. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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Review

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334 KiB  
Review
Activities and Effects of Ergot Alkaloids on Livestock Physiology and Production
by James L. Klotz
Toxins 2015, 7(8), 2801-2821; https://doi.org/10.3390/toxins7082801 - 27 Jul 2015
Cited by 118 | Viewed by 10151
Abstract
Consumption of feedstuffs contaminated with ergot alkaloids has a broad impact on many different physiological mechanisms that alters the homeostasis of livestock. This change in homeostasis causes an increased sensitivity in livestock to perturbations in the ambient environment, resulting in an increased sensitivity [...] Read more.
Consumption of feedstuffs contaminated with ergot alkaloids has a broad impact on many different physiological mechanisms that alters the homeostasis of livestock. This change in homeostasis causes an increased sensitivity in livestock to perturbations in the ambient environment, resulting in an increased sensitivity to such stressors. This ultimately results in large financial losses in the form of production losses to livestock producers around the world. This review will focus on the underlying physiological mechanisms that are affected by ergot alkaloids that lead to decreases in livestock production. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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181 KiB  
Review
Analysis of Ergot Alkaloids
by Colin Crews
Toxins 2015, 7(6), 2024-2050; https://doi.org/10.3390/toxins7062024 - 03 Jun 2015
Cited by 65 | Viewed by 13892
Abstract
The principles and application of established and newer methods for the quantitative and semi-quantitative determination of ergot alkaloids in food, feed, plant materials and animal tissues are reviewed. The techniques of sampling, extraction, clean-up, detection, quantification and validation are described. The major procedures [...] Read more.
The principles and application of established and newer methods for the quantitative and semi-quantitative determination of ergot alkaloids in food, feed, plant materials and animal tissues are reviewed. The techniques of sampling, extraction, clean-up, detection, quantification and validation are described. The major procedures for ergot alkaloid analysis comprise liquid chromatography with tandem mass spectrometry (LC-MS/MS) and liquid chromatography with fluorescence detection (LC-FLD). Other methods based on immunoassays are under development and variations of these and minor techniques are available for specific purposes. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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2908 KiB  
Review
Genetics, Genomics and Evolution of Ergot Alkaloid Diversity
by Carolyn A. Young, Christopher L. Schardl, Daniel G. Panaccione, Simona Florea, Johanna E. Takach, Nikki D. Charlton, Neil Moore, Jennifer S. Webb and Jolanta Jaromczyk
Toxins 2015, 7(4), 1273-1302; https://doi.org/10.3390/toxins7041273 - 14 Apr 2015
Cited by 80 | Viewed by 9391
Abstract
The ergot alkaloid biosynthesis system has become an excellent model to study evolutionary diversification of specialized (secondary) metabolites. This is a very diverse class of alkaloids with various neurotropic activities, produced by fungi in several orders of the phylum Ascomycota, including plant pathogens [...] Read more.
The ergot alkaloid biosynthesis system has become an excellent model to study evolutionary diversification of specialized (secondary) metabolites. This is a very diverse class of alkaloids with various neurotropic activities, produced by fungi in several orders of the phylum Ascomycota, including plant pathogens and protective plant symbionts in the family Clavicipitaceae. Results of comparative genomics and phylogenomic analyses reveal multiple examples of three evolutionary processes that have generated ergot-alkaloid diversity: gene gains, gene losses, and gene sequence changes that have led to altered substrates or product specificities of the enzymes that they encode (neofunctionalization). The chromosome ends appear to be particularly effective engines for gene gains, losses and rearrangements, but not necessarily for neofunctionalization. Changes in gene expression could lead to accumulation of various pathway intermediates and affect levels of different ergot alkaloids. Genetic alterations associated with interspecific hybrids of Epichloë species suggest that such variation is also selectively favored. The huge structural diversity of ergot alkaloids probably represents adaptations to a wide variety of ecological situations by affecting the biological spectra and mechanisms of defense against herbivores, as evidenced by the diverse pharmacological effects of ergot alkaloids used in medicine. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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447 KiB  
Review
Ergot Alkaloids Produced by Endophytic Fungi of the Genus Epichloë
by Philippe Guerre
Toxins 2015, 7(3), 773-790; https://doi.org/10.3390/toxins7030773 - 06 Mar 2015
Cited by 62 | Viewed by 10657
Abstract
The development of fungal endophytes of the genus Epichloë in grasses results in the production of different groups of alkaloids, whose mechanism and biological spectrum of toxicity can differ considerably. Ergot alkaloids, when present in endophyte-infected tall fescue, are responsible for “fescue toxicosis” [...] Read more.
The development of fungal endophytes of the genus Epichloë in grasses results in the production of different groups of alkaloids, whose mechanism and biological spectrum of toxicity can differ considerably. Ergot alkaloids, when present in endophyte-infected tall fescue, are responsible for “fescue toxicosis” in livestock, whereas indole-diterpene alkaloids, when present in endophyte-infected ryegrass, are responsible for “ryegrass staggers”. In contrast, peramine and loline alkaloids are deterrent and/or toxic to insects. Other toxic effects in livestock associated with the consumption of endophyte-infected grass that contain ergot alkaloids include the “sleepy grass” and “drunken horse grass” diseases. Although ergovaline is the main ergopeptine alkaloid produced in endophyte-infected tall fescue and is recognized as responsible for fescue toxicosis, a number of questions still exist concerning the profile of alkaloid production in tall fescue and the worldwide distribution of tall fescue toxicosis. The purpose of this review is to present ergot alkaloids produced in endophyte-infected grass, the factors of variation of their level in plants, and the diseases observed in the mammalian species as relate to the profiles of alkaloid production. In the final section, interactions between ergot alkaloids and drug-metabolizing enzymes are presented as mechanisms that could contribute to toxicity. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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784 KiB  
Review
Biology, Genetics, and Management of Ergot (Claviceps spp.) in Rye, Sorghum, and Pearl Millet
by Thomas Miedaner and Hartwig H. Geiger
Toxins 2015, 7(3), 659-678; https://doi.org/10.3390/toxins7030659 - 25 Feb 2015
Cited by 104 | Viewed by 18887
Abstract
Ergot is a disease of cereals and grasses caused by fungi in the genus Claviceps. Of particular concern are Claviceps purpurea in temperate regions, C. africana in sorghum (worldwide), and C. fusiformis in pearl millet (Africa, Asia). The fungi infect young, usually [...] Read more.
Ergot is a disease of cereals and grasses caused by fungi in the genus Claviceps. Of particular concern are Claviceps purpurea in temperate regions, C. africana in sorghum (worldwide), and C. fusiformis in pearl millet (Africa, Asia). The fungi infect young, usually unfertilized ovaries, replacing the seeds by dark mycelial masses known as sclerotia. The percentage of sclerotia in marketable grain is strictly regulated in many countries. In winter rye, ergot has been known in Europe since the early Middle Ages. The alkaloids produced by the fungus severely affect the health of humans and warm-blooded animals. In sorghum and pearl millet, ergot became a problem when growers adopted hybrid technology, which increased host susceptibility. Plant traits reducing ergot infection include immediate pollination of receptive stigmas, closed flowering (cleistogamy), and physiological resistance. Genetic, nonpollen-mediated variation in ergot susceptibility could be demonstrated in all three affected cereals. Fungicides have limited efficacy and application is weather dependent. Sorting out the sclerotia from the harvest by photocells is expensive and time consuming. In conclusion, molecular-based hybrid rye breeding could improve pollen fertility by introgressing effective restorer genes thus bringing down the ergot infection level to that of conventional population cultivars. A further reduction might be feasible in the future by selecting more resistant germplasm. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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1146 KiB  
Review
Diversification of Ergot Alkaloids in Natural and Modified Fungi
by Sarah L. Robinson and Daniel G. Panaccione
Toxins 2015, 7(1), 201-218; https://doi.org/10.3390/toxins7010201 - 20 Jan 2015
Cited by 47 | Viewed by 9075
Abstract
Several fungi in two different families––the Clavicipitaceae and the Trichocomaceae––produce different profiles of ergot alkaloids, many of which are important in agriculture and medicine. All ergot alkaloid producers share early steps before their pathways diverge to produce different end products. EasA, an oxidoreductase [...] Read more.
Several fungi in two different families––the Clavicipitaceae and the Trichocomaceae––produce different profiles of ergot alkaloids, many of which are important in agriculture and medicine. All ergot alkaloid producers share early steps before their pathways diverge to produce different end products. EasA, an oxidoreductase of the old yellow enzyme class, has alternate activities in different fungi resulting in branching of the pathway. Enzymes beyond the branch point differ among lineages. In the Clavicipitaceae, diversity is generated by the presence or absence and activities of lysergyl peptide synthetases, which interact to make lysergic acid amides and ergopeptines. The range of ergopeptines in a fungus may be controlled by the presence of multiple peptide synthetases as well as by the specificity of individual peptide synthetase domains. In the Trichocomaceae, diversity is generated by the presence or absence of the prenyl transferase encoded by easL (also called fgaPT1). Moreover, relaxed specificity of EasL appears to contribute to ergot alkaloid diversification. The profile of ergot alkaloids observed within a fungus also is affected by a delayed flux of intermediates through the pathway, which results in an accumulation of intermediates or early pathway byproducts to concentrations comparable to that of the pathway end product. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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732 KiB  
Review
Biosynthetic Pathways of Ergot Alkaloids
by Nina Gerhards, Lisa Neubauer, Paul Tudzynski and Shu-Ming Li
Toxins 2014, 6(12), 3281-3295; https://doi.org/10.3390/toxins6123281 - 10 Dec 2014
Cited by 91 | Viewed by 13732
Abstract
Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids. The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloë, Penicillium and Aspergillus species. According to their structures, ergot alkaloids can be divided into three groups: clavines, lysergic [...] Read more.
Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids. The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloë, Penicillium and Aspergillus species. According to their structures, ergot alkaloids can be divided into three groups: clavines, lysergic acid amides and peptides (ergopeptines). All of them share the first biosynthetic steps, which lead to the formation of the tetracyclic ergoline ring system (except the simplest, tricyclic compound: chanoclavine). Different modifications on the ergoline ring by specific enzymes result in an abundance of bioactive natural products, which are used as pharmaceutical drugs or precursors thereof. From the 1950s through to recent years, most of the biosynthetic pathways have been elucidated. Gene clusters from several ergot alkaloid producers have been identified by genome mining and the functions of many of those genes have been demonstrated by knock-out experiments or biochemical investigations of the overproduced enzymes. Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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