S109: Differential Production of Natural Products from a Wild type and Two Mutant Aspergillus nidulans Strains

Genome sequencing has identified the vast biosynthetic potential microorganisms possess, but also determined that only a fraction of these secondary metabolites (SMs) have been produced and identified. Therefore, drug discovery from microorganisms has turned to genetic, chemical epigenetic, and mechanical manipulations in effort to express previously silent SM clusters. In line with this effort was the identification of small molecule differences from one wild type and two mutant (OE:laeA and ΔlaeA) Aspergillus nidulans strains. The hypothesis tested was that laeA globally regulates SM biosynthesis, i.e. OE:laeA strain produces previously silent SMs and ΔlaeA turns off SM biosynthesis. Limited natural products studies have been completed of these strains and a thorough evaluation including quantification and identification of SM differences between these strains was performed.

Also investigated was the role laeA mutation plays in histone acetylation and methylation. The second hypothesis tested was that laeA induces changes in histone methylation and was proposed based on the exact alignment of a S-adenosylmethionine (SAM) binding motif found in histone methyltransferases and the laeA gene. This hypothesis was tested by gauging histone modifications using two platforms: 1) a “top down” proteomics approach that utilizes FTICR-MS to detect global histone acetylation and methylation changes and 2) a “bottom up” approach that employs triple quadrupole (QqQ) MS of histone peptides to identify the degree of residue methylation. Together, histone architecture changes of the three fungal strains were distinguished using MS techniques and corroborated with changes in SM production.