Biotechnology and genetics of ergot alkaloids

Abstract

Ergot alkaloids, i.e. ergoline-derived toxic metabolites, are produced by a wide range of fungi, predominantly by members of the grass-parasitizing family of the Clavicipitaceae. Naturally occurring alkaloids like the D-lysergic acid amides, produced by the "ergot fungus" Claviceps purpurea, have been used as medicinal agents for a long time. The pharmacological effects of the various ergot alkaloids and their derivatives are due to the structural similarity of the tetracyclic ring system to neurotransmitters such as noradrenaline, dopamine or serotonin. In addition to "classical" indications, e.g. migraine or blood pressure regulation, there is a wide spectrum of potential new applications of this interesting group of compounds. The biotechnology of ergot alkaloids has a long tradition, and efficient parasitic and submerse production processes have been developed; the biochemistry of the pathway and the physiology of production have been worked out in detail. The recent identification of a cluster of genes involved in ergot alkaloid biosynthesis in C. purpurea and the availability of molecular genetic techniques allow the development of strategies for rational drug design of ergoline-related drugs by enzyme engineering and by biocombinatorial approaches.

Biosynthesis and Accumulation of Ergoline Alkaloids in a Mutualistic Association between Ipomoea asarifolia (Convolvulaceae) and a Clavicipitalean Fungus

“…The alkaloids confer environmental tolerance, fitness, drought resistance, insecticidal activity, and feed deterrence to their monocotyledonous plants. Books (Rehacek and Sajdl, 1990;White et al, 2003;Hofmann, 2006) and many reviews (Bush et al, 1997;Groeger and Floss, 1998;Malinowski and Belesky, 2000;Tudzynski et al, 2001;Clay and Schardl, 2002;Keller and Tudzynski, 2002;Schardl and Craven, 2003;Clay, 2004;Moon et al, 2004;Schardl et al, 2004Schardl et al, , 2006Tudzynski and Scheffer, 2004;Bacon and Lyons, 2005;Bischoff and White, 2005;Schardl and Leuchtmann, 2005) testify to the role of ergoline alkaloids in ecological, agronomical, genetic, biochemical, pharmacological, and anthropological research.…”

“…Another remarkable feature of ergoline alkaloids is their disjointed distribution in nature: They occur in ascomycetes belonging to the genera Claviceps, Aspergillus, and Penicillium, in the dicotyledonous plant families Convolvulaceae and Polygalaceae (Groeger and Floss, 1998), and were even isolated from an animal, a tunicate representing a Eudistoma species (Makarieva et al, 1999).The occurrence of ergoline alkaloids in taxonomically unrelated taxa was assumed to be due to a horizontal transfer of genes encoding the ergoline alkaloid biosynthetic pathway (Groeger and Floss, 1998;Tudzynski et al, 2001;Clay and Schardl, 2002;Fig. 1).…”

“…The gene (dmaW) encoding this enzyme was cloned from Claviceps purpurea and Claviceps fusiformis (Tsai et al, 1995;Tudzynski et al, 1999), Neotyphodium Lp1 (Wang et al, 2004), Neotyphodium lolii (Fleetwood et al, 2007), and Aspergillus fumigatus (Coyle and Panaccione, 2005;Unsoeld and Li, 2005). The sequence information obtained was used to analyze the adjacent DNA, revealing that dmaW is part of a gene cluster (Tudzynski et al, 2001). This cluster has been extended by Haarmann et al (2005).…”

Endophytes: exploiting biodiversity for the improvement of natural product-based drug discovery

“…Due to their long biotechnological tradition, with manifold applications in therapy (Tudzynski et al 2001), the physiology and biochemistry of ergopeptine formation have been studied in minute detail (Floss 1976;Socic and Gaberc-Porekar 1992;Gro¨ger and Floss 1998). Nevertheless, an uncomfortable premonition of scar- Figure 11.…”

“…Thus, it has been postulated that ergopeptines are not typical of the Ascomycota, the Poaceae or the Convolvulaceae alone, but, in contrast, they are very likely to prove a trait of a clavicipitaceous fungal taxon capable of colonizing certain Figure 13. The ergot alkaloid biosynthetic pathway; biosynthesis of lysergic acid (a) and further ergopeptine formation, as exemplified by ergotamine (b) (Tudzynski et al 1999(Tudzynski et al , 2001). …”