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BEYOND: establishing a fungal cell factory for recombinant protein production

Abstract

Filamentous fungi are capable of producing and secreting a variety of enzymes. Aspergillus sp. and Trichoderma sp. are the major fungal cell factories for industrial enzyme production. Aspergillus oryzae is recognized as GRAS (generally regarded as a safe organism) and has the ability to secrete a high titer of proteins. Therefore, A. oryzae has been used as a low-cost microbial cell factory for the production of recombinant proteins and has the potential to be engineered to boost the secretory pathway. The overall goal is to establish the filamentous fungus A. oryzae as a robust and economically viable microbial cell factory for the production of recombinant proteins for different applications. To do that, we want to harness the synthetic biology concept (learn, design, build and test) combining systems biology, fungal genetic engineering, selection of recombinant proteins with biotechnological applications, bioprocess design, and techno-economical analysis. To achieve that, this project is divided into five aims: (Aim 1) Induction of A. oryzae secretory pathway using Brazilian agro-industrial residues; (Aim 2) Removal of host secreted proteins by multiplex gene deletion; (Aim 3) Production of recombinant proteins with biotechnological applications; (Aim 4) Evaluation of recombinant proteins productivity and function; and (Aim 5) Fungal strains fermentation and techno-economic analysis. We propose to work with three groups of proteins: (1) lytic polysaccharide monooxygenases (LPMOs); (2) Plastic-Active enZymes (PAZymes); and (3) alternative proteins applied to the production of plant-based and cultivated meat. Assuming our team integrated work will result in a robust A. oryzae engineered strain producing high titers of different recombinant proteins using an agro-industrial residue as inducer, multiomics experiments (transcriptome, proteome and metabolome) will be carried out to understand how the recombinant strains adapt to high demand for the secretory pathway. These data will be used to build a genome-scale metabolic model (GEM) for A. oryzae, which will allow the planning of new mutations for genetic improvement of the strain. (AU)

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