Combining metabolic engineering with chemical synthesis; accessing natural product libraries
Advances in the field of Metabolic Engineering (occasionally termed Synthetic Biology) along with the identification and characterisation of gene clusters encoding for the biosynthesis of natural products have allowed for the manipulation of biosynthetic pathways. The inactivation of the biosynthesis of key building blocks on gene level generates mutants of the microbial producer strains which are unable to form the natural product without external supplementation of those key intermediates. Accordingly, analogues of biosynthetic intermediates can be fed to the deficiency mutant, thus probing the biosynthetic machinery for its flexibility and ideally producing novel secondary metabolite with structural alterations dictated by the supplemented intermediate. This concept is termed mutational biosynthesis or in short mutasynthesis.
In our research group mutasynthesis is successfully exploited for the production of novel ansamitocins employing a mutant strain of Actinosynnema pretiosum unable to form the aromatic starter unit typical of all ansamycin antibiotics (geldanamycin, rifamycin, ansatrienin).
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