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      Lolitrem B and Indole Diterpene Alkaloids Produced by Endophytic Fungi of the Genus Epichloë and Their Toxic Effects in Livestock

      review-article
      Toxins
      MDPI
      alkaloids, endophytic fungi, Epichloë, lolitrem B, mycotoxins, livestock, toxicology, staggers

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          Abstract

          Different group of alkaloids are produced during the symbiotic development of fungal endophytes of the genus Epichloë in grass. The structure and toxicity of the compounds vary considerably in mammalian herbivores and in crop pests. Alkaloids of the indole-diterpene group, of which lolitrem B is the most toxic, were first characterized in endophyte-infected perennial ryegrass, and are responsible for “ryegrass staggers.” Ergot alkaloids, of which ergovaline is the most abundant ergopeptide alkaloid produced, are also found in ryegrass, but generally at a lower rate than lolitrem B. Other alkaloids such as lolines and peramine are toxic for crop pests but have weak toxicological properties in mammals. The purpose of this review is to present indole-diterpene alkaloids produced in endophyte infected ryegrass from the first characterization of ryegrass staggers to the determination of the toxicokinetics of lolitrem B and of their mechanism of action in mammals, focusing on the different factors that could explain the worldwide distribution of the disease. Other indole diterpene alkaloids than lolitrem B that can be found in Epichloë infected ryegrass, and their tremorgenic properties, are presented in the last section of this review.

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          Most cited references116

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          Loline alkaloids: Currencies of mutualism.

          Several species of Lolium and other cool-season grasses (Poaceae subfamily Pooideae) tend to harbor symbiotic, seed-transmitted, fungi that enhance their fitness by various means. These fungal endophytes--species of Neotyphodium or Epichloë (Clavicipitaceae)--are known for production of antiherbivore metabolites such as the bioprotective loline alkaloids. Lolines are saturated pyrrolizidines with an exo-1-amine and an ether bridge between C-2 and C-7. The ether bridge is an unusual feature for a biogenic compound in that it links two bridgehead carbon atoms. Much of the loline-biosynthetic pathway has been elucidated by administering isotopically labeled precursors to fungal cultures and by comparisons of loline biosynthesis genes to known gene families. The first step appears to be an unusual gamma-substitution reaction involving an enzyme related to O-acetylhomoserine (thiol) lyase, but which uses the secondary amine of L-proline rather than a sulfhydryl group as the nucleophile. The strained ether bridge is added after formation of the pyrrolizidine rings. Lolines with dimethylated or acylated 1-amines have insect antifeedant and insecticidal activities comparable to nicotine, but little or no toxicity to mammals. Considering the surprising abundance of lolines in some grass-endophyte symbiota, possible additional effects on plant stress tolerance and physiology are worth future consideration. In this review, we discuss the history of loline discovery, methods of analysis, biological activities and distribution in nature, as well as progress on the genetics and biochemistry of their biosynthesis, and on the chemical synthesis of these alkaloids.
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            An association of a Lolium endophyte with ryegrass staggers.

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              High nitrogen supply and carbohydrate content reduce fungal endophyte and alkaloid concentration in Lolium perenne.

              The relationship between cool-season grasses and fungal endophytes is widely regarded as mutualistic, but there is growing uncertainty about whether changes in resource supply and environment benefit both organisms to a similar extent. Here, we infected two perennial ryegrass (Lolium perenne) cultivars (AberDove, Fennema) that differ in carbohydrate content with three strains of Neotyphodium lolii (AR1, AR37, common strain) that differ intrinsically in alkaloid profile. We grew endophyte-free and infected plants under high and low nitrogen (N) supply and used quantitative PCR (qPCR) to estimate endophyte concentrations in harvested leaf tissues. Endophyte concentration was reduced by 40% under high N supply, and by 50% in the higher sugar cultivar. These two effects were additive (together resulting in 75% reduction). Alkaloid production was also reduced under both increased N supply and high sugar cultivar, and for three of the four alkaloids quantified, concentrations were linearly related to endophyte concentration. The results stress the need for wider quantification of fungal endophytes in the grassland-foliar endophyte context, and have implications for how introducing new cultivars, novel endophytes or increasing N inputs affect the role of endophytes in grassland ecosystems.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                15 February 2016
                February 2016
                : 8
                : 2
                : 47
                Affiliations
                Université de Toulouse, INP, ENVT, UR Mycotoxicologie, F-31076 Toulouse, France; p.guerre@ 123456envt.fr ; Tel.: +33-056-119-3840
                Article
                toxins-08-00047
                10.3390/toxins8020047
                4773800
                26891327
                dc09d588-740a-44db-b811-2da67da30ba6
                © 2016 by the author; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 January 2016
                : 03 February 2016
                Categories
                Review

                Molecular medicine
                alkaloids,endophytic fungi,epichloë,lolitrem b,mycotoxins,livestock,toxicology,staggers
                Molecular medicine
                alkaloids, endophytic fungi, epichloë, lolitrem b, mycotoxins, livestock, toxicology, staggers

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