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Exploiting the therapeutic potential of secondary metabolites from fungi

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Biotechnology has brought about a revolution in drug manufacturing since its inception. Many life-saving drugs have spun out of biotech companies over the past few decades. However, there is still a vast body of unexplored compounds such as the fungal secondary metabolites that have the potential to prolong human lifespan. The production of these secondary metabolites in most cases involves a large backbone enzyme that contains multiple catalytic domains. One of the goals is to establish a modular system of domain shuffling to generate a plethora of novel enzymes with new and improved functionalities. The possibilities are endless as there is a myriad of different domains from many fungi that can be added, removed, reordered or exchanged in this synthetic biology approach. The production of lovastatin, a drug used in lowering LDL cholesterol for patients suffering from cardiovascular disease, has been chosen as a proof of principle. Currently, it is produced in the fungi Aspergillus terreus, which also produces less desirable toxins. The aim is to transfer the entire lovastatin metabolic pathway from A. terreus into a GRAS organism like Aspergillus niger, which is closely related. A. niger is amenable to genetic engineering, has a high protein secretion capacity and produces high amounts of organic acids. One of the main enzymes involved in the production of lovastatin is the 277kDa LovB enzyme, which contains 7 different catalytic domains. Prior studies on this pathway provide a good insight into the catalytic mechanisms of these individual domains. The individual domains have been mapped by homology modeling and are found to be well defined as well as often in a sequential order, which makes the modular approach more feasible.

In addition to the modularity approach, a toolkit for A. niger is also being created, consisting of an ATP and a pH biosensor that can be targeted to specific compartments with the use of signal peptides, actin and septa GFP fusions to visualize the cytoskeleton and the junctions between adjacent cells, and chromoproteins that can serve as secondary selection markers. These tools allow one to obtain insight in cellular economy, physiology and architecture, which can be used to optimize the production processes in A. niger.