Fungal natural products—the mushroom perspective

Among the first documented studies on the chemistry of fungal natural products were descriptions of quinoid pigments, i.e., the L-tyrosineand L-phenylalaninederived terphenylquinones atromentin and polyporic acid, respectively. The isolation of these compounds from mushroom fruiting bodies (basidiomes) was published around 1877 by Stahlschmidt and Thörner. Ever since, organic chemists embraced basidiomycetes as a prolific source of bioactive compounds and investigated these fungi with regard to compound isolation, structure elucidation, and synthesis (Gill and Steglich, 1987; Zhou and Liu, 2010; De Silva et al., 2013 and previous reviews referenced therein, Lorenzen and Anke, 1998; Richter et al., in press). Mushrooms seem to be particularly talented in producing unique terpenoids, and the molecular background behind the biosynthesis of some of those compounds has only recently been elucidated (Quin et al., 2014). Prominent examples of basidiomycete metabolites for lead structures in agrochemistry and drug research are, among others, the strobilurins, i.e., agriculturally used ßmethoxyacrylate fungicides from cultures of Mycena, Oudemansiella, Strobilurus, Xerula and several other basidiomycete genera (Sauter et al., 1999, Figure 1). Other examples are the pleuromutilins, the illudins, and the omphalotins (Figure 1). The pleuromutilins from cultures of species that are now placed in the genera Clitopilus and Omphalina served as scaffold for the development of the semisynthetic antibacterial antibiotic retapamulin (Kirst, 2013) which is clinically used for topical treatment of infections with Staphylococcus aureus. The illudins from Lampteromyces and Omphalotus species (Omphalotaceae) are sesquiterpenes featuring an unusual cyclopropane ring and are currently developed as anticancer drugs (Tanasova and Sturla, 2012). The omphalotins are cyclopeptides with pronounced nematicidal activites against root knot nematodes (Büchel et al., 1998), which are also exclusively found in the Omphalotaceae. Recently, the blazeispirols from Agaricus subrufescens were discovered as strong and selective agonists of the Liver X receptor (LXR alpha). Concurrently, relevant in vivo effects of blazeispirols in a mouse model were observed which might give rise to the development of a new antihypercholesterolemic agent from cultures of a medicinal mushroom (Grothe et al., 2011). The above examples illustrate that basidiomycete secondary metabolomes merit further exploration. Perhaps fortunately for coming generations of Ph.D. students, the realm of basidiomycete metabolites is still underexplored, even after decades of intensive research to isolate and structurally elucidate compounds. This is also evident by the fact that toxic principles of mushrooms which repeatedly led to poisonings were identified only recently (Figure 1). Recent advances pertain to Trogia venenata fruiting bodies, in which the toxic 2R-amino-5-hexynoic acid and related compounds were found (Zhou et al., 2012). Cycloprop-2-ene carboxylic acid causing rhabdomyolysis was isolated from Russula subnigricans, a toxic mushroom native to East Asia (Matsuura et al., 2009). Furthermore, saponaceolide toxins with their unusual molecular skeleton were discovered in Tricholoma terreum (Yin et al., 2014). For basidiomycetes, the genomic era set in later than for ascomycetes, and in numbers of genome projects the former are still lagging behind the latter. Still, the available genomic data impacted natural product research as it reveals a stimulating disparity: the number of natural product genes, best reflected by the number of genes for polyketide synthases and peptide synthetases exceeds the number of known compounds by far— even after decades of chemical research. The “house eater” fungus Serpula lacrymans encodes 21 PKS and NRPS genes (Eastwood et al., 2011), the average number of PKS genes per basidiomycete genome is four, according to a survey of 35 mostly saprotrophic species (Lackner et al., 2012). The wealth of natural product biosynthesis genes in a given species contrasts the few compounds known from the same species. This situation is reminiscent of what was found for ascomycete genomes years ago, e.g., for the genera Aspergillus, Penicillium, Fusarium, and others (Keller et al., 2005; Desjardins and Proctor, 2007; Sanchez et al., 2012). However, the course research has taken (and will be taking) to make as much sense as possible out of the genomic data is quite different with basidiomycetes. This is due to a number of reasons that contrast the situation with ascomycetes.