Chapter 15 : Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis

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With respect to fungal pathogenesis and virulence, fungal secondary metabolites are primary virulence factors in several fungus-plant interactions. This chapter explores the current state of knowledge on the production of secondary metabolites by the opportunistic human pathogen Aspergillus fumigatus. Several types of secondary metabolites have been isolated from A. fumigatus in vitro cultures, including fumitremorgins, verruculogen, fumigaclavines, fumagillin, helvolic acid, and gliotoxin, among other, less-studied compounds. Importantly, gliotoxin has been detected in the serum of patients with invasive pulmonary aspergillosis (IPA) and in experimental murine models of IPA. Overexpression of the nonribosomal peptide synthetase (NRPS) ftmA in A. fumigatus AF293.1 and A. nidulans resulted in accumulation of brevianamide F, the likely precursor of fumitremorgin biosynthesis. Like many other A. fumigatus-produced secondary metabolites, the potential role of helvolic acid in aspergillosis is unknown. Production of secondary metabolites is an energetically costly process involving many enzymatic steps. In fungi, signals generated in response to the environment are typically relayed through DNA-binding Cys2His2 zinc-finger proteins, including CreA for carbon signaling, AreA for nitrogen signaling, and PacC for pH signaling. Insight into signaling pathways linking growth, development, and secondary metabolism came from a key study in A. nidulans showing heterotrimeric G-protein activation simultaneously inhibits sporulation and production of the mycotoxin sterigmatocystin while promoting vegetative growth. Fungal secondary metabolites are important biomolecules with significant biological activities.

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
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Image of Figure 1.
Figure 1.

Secondary metabolites produced by A. fumigatus. Chemical structures were obtained from the PubChem project http://pubchem.ncbi.nlm.nih.gov/

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
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Image of Figure 2.
Figure 2.

Regulation of a hypothetical secondary metabolite gene cluster. This figure illustrates modes of regulation of production for a hypothetical secondary metabolite based on known regulatory mechanisms for gliotoxin, aflatoxin, sterigmatocystin, and others. A cluster-specific regulatory gene located within the cluster is activated by LaeA and in turn activates expression of the rest of the cluster genes, leading to biosynthesis of the metabolite product, which then may act to promote expression of the cluster in a positive feedback mechanism. Cluster expression is repressed by the chromatin-modifying proteins ClrD, HepA, and HdaA. G-protein signaling activates PKA, which suppresses metabolite production by inhibiting expression of laeA and the in-cluster transcription factor gene and also by inactivation of its protein product via phosphorylation. Environmental signals, such as carbon and nitrogen sources, pH, and light, may alter production of this metabolite through the actions of proteins such as CreA, PacC, AreA, and VeA.

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15
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Table 1.

Pathogenesis studies of gliotoxin-deficient A. fumigatus strains in murine models of IPA

Citation: Cramer, Jr. R, Shwab E, Keller N. 2009. Genetic Regulation of Aspergillus Secondary Metabolites and Their Role in Fungal Pathogenesis, p 185-199. In Latgé J, Steinbach W (ed), and Aspergillosis. ASM Press, Washington, DC. doi: 10.1128/9781555815523.ch15

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