1. Secondary Metabolite Categories
Fungal secondary metabolites are categorized
according to their biosynthesis in the four
major groups polyketides, non-ribosomal peptides, terpenes, and indole alkaloids but comprise also mixed forms or smaller groups
(Fig. 8.1b; Keller et al. 2005).
Polyketides are the most abundant secondary metabolites in fungi and are synthesized by
type I polyketide synthases (PKS). Type I PKS
are multi-domain enzymes similar to eukaryotic fatty acid synthases, consisting of the
essential ketoacyl CoA synthase (KS), acyltransferase (AT), acyl carrier protein
(ACP) domains, and a termination domain
(Keller et al. 2005). Additionally, they can harbor variable domains like dehydratase, ketoreductase, enoylreductase, or methyltransferase
domains. The domains are arranged in a module. Whereas bacterial PKS usually have multiple modules, the fungal PKS typically carries
only one module, which can be used iteratively.
The precursors for the biosynthesis of polyketides are usually acetyl coenzyme A (acetylCoA) and malonyl-CoA, but also propionylCoA or methylmalonyl-CoA are used. During
the starting stage of polyketide synthesis, the
precursors are loaded onto the starter domains
KS and ACP, catalyzed by the AT domain. In
the elongation stage, these loaded precursors
are condensed by decarboxylative condensation similar to the fatty acid synthesis, resulting
in a polyketide chain. By loading of another
starter unit, the next cycle starts, and the polyketide chain is elongated by the new starter unit
similarly. The control of how many cycles are
performed is not yet understood. Finally, the
polyketide chain is released from the enzyme
by the termination domain (Keller et al. 2005).
Among the class of polyketides are several
products that demonstrate the tight link
between developmental processes and secondary metabolism by fulfilling survival or longevity tasks, inducing sexual development as
hormones or conferring virulence. Typical
examples are melanins, zearalenone, and Ttoxin. Melanins are pigments that can be
incorporated into the fungal cell wall or
secreted to the environment. They strengthen
the cell wall, protect the fungal spores from UV
light, or can inhibit hydrolytic enzymes produced by other microorganisms (Toledo et al.
2017). Zearalenone, an estrogenic polyketide
produced exclusively by different Fusarium
species, is a sex hormone. Whereas loss of zearalenone prevents sexual reproduction, its addition can positively or negatively affect sexual
development, depending on the applied concentrations (Wolf and Mirocha 1977). T-toxin
is a polyketide produced by Cochliobolus heterostrophus, a necrotrophic fungal plant pathogen that causes southern corn leaf blight in
maize. It is connected with high virulence
2
in maize cultivars carrying the “Texas male
sterile cytoplasm”, but it is not required for
pathogenicity
3 itself. It contributes to virulence
by disrupting the mitochondrial activity (Stergiopoulos et al. 2013).
Non-ribosomal peptides are peptides that
are produced from proteinogenic and nonproteinogenic amino acids by enzymes called
non-ribosomal peptide synthetases (NRPS)
without the use of ribosomes. NRPS are multidomain and multi-modular enzymes. Each
module contains an adenylation domain for
the recognition of the amino acid, a peptidyl
carrier domain for the activation and covalent
binding of the amino acid to the phosphopantetheine transferase cofactor (PPTase) and a
condensation domain for peptide formation.
The final peptide is usually released by a thioesterase domain at the C-terminus of the enzyme.
The diversity of non-ribosomal peptides
derives from cyclization or branching of peptides. Among them are, for instance, the antibiotic penicillin, siderophores, and gliotoxin.
Siderophores are iron-chelating compounds
produced for the uptake and storage of iron
ions. Usually they contain hydroxamate groups
that form strong iron(III) binding bidentates.
Most filamentous fungi and some yeasts, except
for the model organisms S. cerevisiae or C.
albicans, produce siderophores. A fine-tuned
system between iron uptake and storage is necessary to prevent the fungus from iron starva2 Virulence ¼ severity of a disease caused by a pathogen.
3 Pathogenicity ¼ ability of a pathogen to cause a disease.
176
J. Gerke et al.
Fungal secondary metabolites are categorized
according to their biosynthesis in the four
major groups polyketides, non-ribosomal peptides, terpenes, and indole alkaloids but comprise also mixed forms or smaller groups
(Fig. 8.1b; Keller et al. 2005).
Polyketides are the most abundant secondary metabolites in fungi and are synthesized by
type I polyketide synthases (PKS). Type I PKS
are multi-domain enzymes similar to eukaryotic fatty acid synthases, consisting of the
essential ketoacyl CoA synthase (KS), acyltransferase (AT), acyl carrier protein
(ACP) domains, and a termination domain
(Keller et al. 2005). Additionally, they can harbor variable domains like dehydratase, ketoreductase, enoylreductase, or methyltransferase
domains. The domains are arranged in a module. Whereas bacterial PKS usually have multiple modules, the fungal PKS typically carries
only one module, which can be used iteratively.
The precursors for the biosynthesis of polyketides are usually acetyl coenzyme A (acetylCoA) and malonyl-CoA, but also propionylCoA or methylmalonyl-CoA are used. During
the starting stage of polyketide synthesis, the
precursors are loaded onto the starter domains
KS and ACP, catalyzed by the AT domain. In
the elongation stage, these loaded precursors
are condensed by decarboxylative condensation similar to the fatty acid synthesis, resulting
in a polyketide chain. By loading of another
starter unit, the next cycle starts, and the polyketide chain is elongated by the new starter unit
similarly. The control of how many cycles are
performed is not yet understood. Finally, the
polyketide chain is released from the enzyme
by the termination domain (Keller et al. 2005).
Among the class of polyketides are several
products that demonstrate the tight link
between developmental processes and secondary metabolism by fulfilling survival or longevity tasks, inducing sexual development as
hormones or conferring virulence. Typical
examples are melanins, zearalenone, and Ttoxin. Melanins are pigments that can be
incorporated into the fungal cell wall or
secreted to the environment. They strengthen
the cell wall, protect the fungal spores from UV
light, or can inhibit hydrolytic enzymes produced by other microorganisms (Toledo et al.
2017). Zearalenone, an estrogenic polyketide
produced exclusively by different Fusarium
species, is a sex hormone. Whereas loss of zearalenone prevents sexual reproduction, its addition can positively or negatively affect sexual
development, depending on the applied concentrations (Wolf and Mirocha 1977). T-toxin
is a polyketide produced by Cochliobolus heterostrophus, a necrotrophic fungal plant pathogen that causes southern corn leaf blight in
maize. It is connected with high virulence
2
in maize cultivars carrying the “Texas male
sterile cytoplasm”, but it is not required for
pathogenicity
3 itself. It contributes to virulence
by disrupting the mitochondrial activity (Stergiopoulos et al. 2013).
Non-ribosomal peptides are peptides that
are produced from proteinogenic and nonproteinogenic amino acids by enzymes called
non-ribosomal peptide synthetases (NRPS)
without the use of ribosomes. NRPS are multidomain and multi-modular enzymes. Each
module contains an adenylation domain for
the recognition of the amino acid, a peptidyl
carrier domain for the activation and covalent
binding of the amino acid to the phosphopantetheine transferase cofactor (PPTase) and a
condensation domain for peptide formation.
The final peptide is usually released by a thioesterase domain at the C-terminus of the enzyme.
The diversity of non-ribosomal peptides
derives from cyclization or branching of peptides. Among them are, for instance, the antibiotic penicillin, siderophores, and gliotoxin.
Siderophores are iron-chelating compounds
produced for the uptake and storage of iron
ions. Usually they contain hydroxamate groups
that form strong iron(III) binding bidentates.
Most filamentous fungi and some yeasts, except
for the model organisms S. cerevisiae or C.
albicans, produce siderophores. A fine-tuned
system between iron uptake and storage is necessary to prevent the fungus from iron starva2 Virulence ¼ severity of a disease caused by a pathogen.
3 Pathogenicity ¼ ability of a pathogen to cause a disease.
176
J. Gerke et al.