Fungal secondary metabolites (SM) are bioactive compounds that are important in fungal ecology and, moreover, both harmful and useful in human endeavors (e.g., as toxins and pharmaceuticals). Recently a nuclear heterocomplex termed the Velvet complex, characterized in the model ascomycete Aspergillus nidulans, was found to be critical for SM production. Deletion of two members of the Velvet complex, laeA and veA, results in near loss of SM and defective sexual spore production in A. nidulans and other species. Using a multicopy-suppressor genetics approach, we have isolated an Aspergillus nidulans gene named rsmA (remediation of secondary metabolism) based upon its ability to remediate secondary metabolism in ⌬laeA and ⌬veA backgrounds. Overexpression of rsmA (OE::rsmA) restores production of sterigmatocystin (ST) (a carcinogenic SM) via transcriptional activation of ST biosynthetic genes. However, defects in sexual reproduction in either ⌬laeA or ⌬veA strains cannot be overcome by OE::rsmA. An intact Velvet complex coupled with an OE::rsmA allele increases SM many fold over the wild-type level, but loss of rsmA does not decrease SM. RsmA encodes a putative bZIP basic leucine zipper-type transcription factor.Secondary metabolites are biologically active compounds that are diverse in structure and often possess either pharmacological or toxic properties. To customize and control the biosynthesis of these natural products, we must understand how secondary metabolites (SM) are regulated. In fungi, SM production is controlled by global transcription factors encoded by genes unlinked to the SM biosynthetic gene clusters. Such genes regulate multiple physiological processes and generally respond to environmental cues such as pH, temperature, and nutrition (27,45). Regulation of many clustered genes is also largely dependent on pathway-specific transcription (18,22,42) and signal transduction pathways that link secondary metabolism with sporulation (13).LaeA is a global regulator of SM in the aspergilli. LaeA, a putative methyltransferase, was first identified in Aspergillus nidulans (5), A. fumigatus (6), and, subsequently, A. flavus (25). Overexpression (OE) of laeA increases the production of multiple metabolites in the aspergilli, whereas deletion of laeA silences expression of SM genes (1,5,8,20). LaeA is thus used as a genomic mining tool, providing a novel method for identifying new SM through microarray and chemical analyses (8,20,34). Moreover, deletion of laeA in A. fumigatus decreases the virulence of this human pathogen (4, 6); similarly, A. flavus laeA deletants are also reduced in virulence on host seed (1, 25). LaeA homologs are also found in other filamentous fungi such as Penicillium chrysogenum and Fusarium fujikuroi, where they control SM, pigmentation, sporulation, and virulence (29,43).Another important SM regulatory protein identified in A. nidulans is encoded by veA, otherwise known as velvet. VeA is a light-dependent regulator governing both development and SM production in several aspergilli (A...

Secondary metabolite (SM) production by fungi is hypothesized to provide some fitness attribute for the producing organisms. However, most SM clusters are "silent" when fungi are grown in traditional laboratory settings, and it is difficult to ascertain any function or activity of these SM cluster products. Recently, the creation of a chromatin remodeling mutant in Aspergillus nidulans induced activation of several cryptic SM gene clusters. Systematic testing of nine purified metabolites from this mutant identified an emodin derivate with efficacy against both human fungal pathogens (inhibiting both spore germination and hyphal growth) and several bacteria. The ability of catalase to diminish this antimicrobial activity implicates reactive oxygen species generation, specifically, the generation of hydrogen peroxide, as the mechanism of emodin hydroxyl activity.