tion or toxicity (Haas 2014). Gliotoxin is
another prominent example of non-ribosomal
peptides. It is a mycotoxin produced by human
pathogens such as Aspergillus fumigatus, Trichoderma spp., and Penicillium spp. It inhibits
the proteasome and prevents NF-kB activation
(see Sect. V.A) as presumed virulence factor of
A. fumigatus by targeting primarily the activity
of neutrophils or other phagocytes of the host
immune system (Scharf et al. 2016).
Terpenes are built up from isoprene units
by terpene synthases (terpene cyclases). The
subgroup of oxygenated forms of terpenes is
called terpenoids. Most of known terpenes
derive from plants, for example, the major constituents of essential oils. In terpene synthesizing fungi, they are produced by the mevalonate
pathway. Prominent examples are the carotenoid pigments, the gibberellin phytohormones
or the trichothecene mycotoxins (SchmidtDannert 2014).
Indole alkaloids are nitrogen-containing
secondary metabolites incorporating one or
more indole or indoline moieties (Xu et al.
2014). Mostly, the indole precursors are tryptophan or related indole-3-glycerol-phosphate.
Tryptophan is prenylated with dimethylallyl
pyrophosphate by dimethylallyl tryptophan
synthases (DMATS). Ergotamine from Claviceps purpurea represents a prominent example
for an indole alkaloid. It works as vasoconstrictor with structural similarity to several neurotransmitters and is medicinally used against
acute migraine attacks (Schardl et al. 2006).
Besides the four main groups, there are
additional classes of fungal secondary metabolites (Fig. 8.1b). Metabolites consisting of combinations of peptides and polyketides (peptidepolyketide hybrids), such as emericellamides
or aspyridone, are formed by PKS-NRPS
hybrids that contain all typical domains of the
single PKS and NRPS (Du et al. 2001). Meroterpenoids are products with a partial terpenoid structure plus a polyketide or a peptide
moiety (Matsuda and Abe 2016). An example
for a meroterpenoid with a polyketide moiety is
dehydroaustinol produced by A. nidulans. The
addition of dehydroaustinol together with the
polyketide diorcinol restores spore formation
of A. nidulans mutants defective in sporulation,
suggesting that these two compounds or derivatives serve as developmental signal for asexual sporulation (Rodrı ´guez-Urra et al. 2012;
Fig. 8.1a). Oxylipins (collectively termed psifactor (precocious sexual inducer)) are oxygenated polyunsaturated fatty acids produced by
oxygenases (Brodhun and Feussner 2011). In
Aspergillus nidulans, three psi factor producing
oxygenases PpoA, PpoB, and PpoC have been
characterized producing mainly hydroxylated
oleic (18:1) and linoleic (18:2) acid. A careful
regulated system of oxylipins is necessary for a
proper balance between asexual and sexual
development (Tsitsigiannis et al. 2004). Besides
these non-volatile oxylipins, also volatile oxylipins exist. They share an eight-carbon scaffold
and are suggested to be involved in fungusinvertebrate interactions (Holighaus and Rohlfs
2018). Isocyanides, which function as chalkophores, contain nitrile groups and are synthesized by isocyanide synthases that can also
occur as hybrids with NRPS. The first characterized isocyanide was xanthocillin, which is
produced, e.g., by Penicillium notatum and by
A. fumigatus (Lim et al. 2018).
2. Secondary Metabolite Clusters Are Often
Silenced and Have to Be Activated for
Analysis in the Laboratory
The large diversity of secondary metabolites is
due to modifications that are performed after
the initial step of building the skeleton. These
include oxidations, cyclizations, methylations,
dehydrations, or reductions. Fungal genes that
are necessary for the biosynthesis of the final
secondary metabolites as well as genes encoding proteins necessary for regulation of the
synthesis or transport of the final metabolite
product are usually, and similarly to genes for
specialized or accessory primary metabolism,
clustered together on one chromosomal locus
(Rokas et al. 2018). The gene clusters enable an
economical production of secondary metabolites due to transcriptional co-regulation. Most
secondary metabolite biosynthetic gene clusters are silenced and are only expressed under
very specific conditions. Especially under laboratory conditions, where the fungus does not
8 Coordination of Fungal Secondary Metabolism and Development
177
another prominent example of non-ribosomal
peptides. It is a mycotoxin produced by human
pathogens such as Aspergillus fumigatus, Trichoderma spp., and Penicillium spp. It inhibits
the proteasome and prevents NF-kB activation
(see Sect. V.A) as presumed virulence factor of
A. fumigatus by targeting primarily the activity
of neutrophils or other phagocytes of the host
immune system (Scharf et al. 2016).
Terpenes are built up from isoprene units
by terpene synthases (terpene cyclases). The
subgroup of oxygenated forms of terpenes is
called terpenoids. Most of known terpenes
derive from plants, for example, the major constituents of essential oils. In terpene synthesizing fungi, they are produced by the mevalonate
pathway. Prominent examples are the carotenoid pigments, the gibberellin phytohormones
or the trichothecene mycotoxins (SchmidtDannert 2014).
Indole alkaloids are nitrogen-containing
secondary metabolites incorporating one or
more indole or indoline moieties (Xu et al.
2014). Mostly, the indole precursors are tryptophan or related indole-3-glycerol-phosphate.
Tryptophan is prenylated with dimethylallyl
pyrophosphate by dimethylallyl tryptophan
synthases (DMATS). Ergotamine from Claviceps purpurea represents a prominent example
for an indole alkaloid. It works as vasoconstrictor with structural similarity to several neurotransmitters and is medicinally used against
acute migraine attacks (Schardl et al. 2006).
Besides the four main groups, there are
additional classes of fungal secondary metabolites (Fig. 8.1b). Metabolites consisting of combinations of peptides and polyketides (peptidepolyketide hybrids), such as emericellamides
or aspyridone, are formed by PKS-NRPS
hybrids that contain all typical domains of the
single PKS and NRPS (Du et al. 2001). Meroterpenoids are products with a partial terpenoid structure plus a polyketide or a peptide
moiety (Matsuda and Abe 2016). An example
for a meroterpenoid with a polyketide moiety is
dehydroaustinol produced by A. nidulans. The
addition of dehydroaustinol together with the
polyketide diorcinol restores spore formation
of A. nidulans mutants defective in sporulation,
suggesting that these two compounds or derivatives serve as developmental signal for asexual sporulation (Rodrı ´guez-Urra et al. 2012;
Fig. 8.1a). Oxylipins (collectively termed psifactor (precocious sexual inducer)) are oxygenated polyunsaturated fatty acids produced by
oxygenases (Brodhun and Feussner 2011). In
Aspergillus nidulans, three psi factor producing
oxygenases PpoA, PpoB, and PpoC have been
characterized producing mainly hydroxylated
oleic (18:1) and linoleic (18:2) acid. A careful
regulated system of oxylipins is necessary for a
proper balance between asexual and sexual
development (Tsitsigiannis et al. 2004). Besides
these non-volatile oxylipins, also volatile oxylipins exist. They share an eight-carbon scaffold
and are suggested to be involved in fungusinvertebrate interactions (Holighaus and Rohlfs
2018). Isocyanides, which function as chalkophores, contain nitrile groups and are synthesized by isocyanide synthases that can also
occur as hybrids with NRPS. The first characterized isocyanide was xanthocillin, which is
produced, e.g., by Penicillium notatum and by
A. fumigatus (Lim et al. 2018).
2. Secondary Metabolite Clusters Are Often
Silenced and Have to Be Activated for
Analysis in the Laboratory
The large diversity of secondary metabolites is
due to modifications that are performed after
the initial step of building the skeleton. These
include oxidations, cyclizations, methylations,
dehydrations, or reductions. Fungal genes that
are necessary for the biosynthesis of the final
secondary metabolites as well as genes encoding proteins necessary for regulation of the
synthesis or transport of the final metabolite
product are usually, and similarly to genes for
specialized or accessory primary metabolism,
clustered together on one chromosomal locus
(Rokas et al. 2018). The gene clusters enable an
economical production of secondary metabolites due to transcriptional co-regulation. Most
secondary metabolite biosynthetic gene clusters are silenced and are only expressed under
very specific conditions. Especially under laboratory conditions, where the fungus does not
8 Coordination of Fungal Secondary Metabolism and Development
177