Studies on the production of fungal polyketides in Aspergillus nidulans using systems biology tools. Aspergillus nidulans

Using genetic engineering tools available for the model organism Aspergillus nidulans, we constructed two recombinant strains; one expressing the model polyketide Penicillium griseofulvum 6-methylsalicylic acid (6-MSA) polyketide synthase gene, and one expressing the 6-MSA gene and overexpressing the native phosphoketolase (phk) for increasing the pool of polyketide precursor levels. The physiology of the recombinant strains and a reference wild type were characterized on glucose, xylose, glycerol and ethanol medium in controlled bioreactors. Glucose was found to be the preferable carbon source for 6-MSA production and 6-MSA titers up to 455 mg/L were achieved. Our findings indicate that overexpression of phk does not directly improve 6-MSA production on glucose but if the lower glycolysis is lowered, it is possible to obtain quite high conversion yields of sugar to 6-MSA. Systems biology tools were employed for in-depth analysis of the metabolic processes. Transcriptome analysis of 6-MSA producing strains on glucose and xylose in the presence and absence of phk overexpression combined with flux and physiology data enabled us to propose a model of phk/6msas interaction describing two different responses influencing 6-MSA production. Overall design: Four strains on two carbon sources