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Chapter 17 : : a Model for Elucidation of Secondary Metabolism

Author: Nancy Keller1
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Affiliations: 1: Department of Plant Pathology, University of Wisconsin–Madison, Madison, WI 53706
Content Type: Monograph
Publication Year: 2006

Category: Fungi and Fungal Pathogenesis

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Abstract:

This chapter reviews the contributions made by to the understanding of fungal secondary metabolism and the ways in which advances in our understanding of this species have spurred parallel studies of . The most thorough insight into fungal secondary metabolite regulation has arisen from studies of the mycotoxin sterigmatocystin (ST) and the antibiotic penicillin in . With possibly the exception of the penicillin metabolic cluster, the most thoroughly examined fungal secondary-metabolite gene clusters are those involved in mycotoxin biosynthesis, particularly the aflatoxin (AF) and ST biosynthetic clusters found in several spp. Coordinate regulation is largely explained by transcriptional control by pathway-specific regulatory factors (e.g., aflR) and global regulatory proteins including transcription factors mediating environmental signals (pH, carbon, and nitrogen) and the cluster-specific methylase, LaeA. Specific oxylipins, e.g., various prostaglandins, are ligands to G-protein-coupled receptors (GPCR), which are important in inflammatory and immune responses in mammals. Interestingly, recent studies have identified three GPCR that impact asexual and sexual spore production, and efforts are under way to determine if Ppo products may be potential ligands for these receptors. PGs, along with leukotrienes, comprise a class of oxylipins called eicosanoids formed from C fatty acids (dihomo-γ-linolenic acid, arachidonic acid, and eicosanopentaenoic acid). Initial studies of and function in indicate a potent role for these secondarymetabolite genes in pathogenesis. A thorough understanding of the function of these and other secondary metabolism genes may assist in the development of future therapeutics.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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Aspergillus nidulans: a Model for Elucidation of Aspergillus fumigatus Secondary Metabolism
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Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
/content/10.1128/9781555815776.ch17.ch17fig01
Figure 1.
ST (A) and gliotoxin (B) gene clusters. The function of each protein is listed. AF, aflatoxin.
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10.1128/9781555815776/f0236-01.gif
Image of Figure 1.
Figure 1.

ST (A) and gliotoxin (B) gene clusters. The function of each protein is listed. AF, aflatoxin.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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Figure 2.
(A) Thin-layer chromatography of organic extracts of the and mutants compared to the wild type (WT). ST, sterigmatocystin standard: G, gliotoxin standard. Note that both mutants are deficient in the production of many metabolites, not just ST () or G (). (B) Northern analysis of sterigmatocystin genes, and , in wild-type and Δ strains at the 12-, 24-, 48-, and 72-h time points. Expression of both genes is repressed in the Δ mutant. Reprinted from reference with permission.
10.1128/9781555815776/f0237-01_thmb.gif
10.1128/9781555815776/f0237-01.gif
Image of Figure 2.
Figure 2.

(A) Thin-layer chromatography of organic extracts of the and mutants compared to the wild type (WT). ST, sterigmatocystin standard: G, gliotoxin standard. Note that both mutants are deficient in the production of many metabolites, not just ST () or G (). (B) Northern analysis of sterigmatocystin genes, and , in wild-type and Δ strains at the 12-, 24-, 48-, and 72-h time points. Expression of both genes is repressed in the Δ mutant. Reprinted from reference with permission.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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Figure 3.
Proposed model of G-protein signaling in regulating sporulation and mycotoxin biosynthesis in spp. Oxylipin acts as a ligand to initiate the G-protein signaling cascade, which can lead to either suppression of toxin formation and sporulation (shown here) or activation of both processes (via different GPCR and different α subunits of the heterotrimeric G proteins). FadA, alpha subunit of a heterotrimeric G protein; FlbA, RGS protein; PkaA, protein kinase A; LaeA, global regulator of secondary metabolites.
10.1128/9781555815776/f0238-01_thmb.gif
10.1128/9781555815776/f0238-01.gif
Image of Figure 3.
Figure 3.

Proposed model of G-protein signaling in regulating sporulation and mycotoxin biosynthesis in spp. Oxylipin acts as a ligand to initiate the G-protein signaling cascade, which can lead to either suppression of toxin formation and sporulation (shown here) or activation of both processes (via different GPCR and different α subunits of the heterotrimeric G proteins). FadA, alpha subunit of a heterotrimeric G protein; FlbA, RGS protein; PkaA, protein kinase A; LaeA, global regulator of secondary metabolites.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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