PATHWAY ENGINEERING IN SECONDARY METABOLITE-PRODUCING ACTINOMYCETES

Actinomycetes represent the microbial group richest in production of v ariable secondary metabolites. These mostly bioactive molecules are th e end products of complex multistep biosynthetic pathways. Recent prog ress in the molecular genetics and biochemistry of the biosynthetic ca pacities of actinomycetes enables first attempts to redesign these pat hways in a directed fashion. However, in contrast to several examples of designed biochemical improvement of primary metabolic processes in microorganisms, none of the products or strains derived from pathway e ngineering in actinomycetes discussed herein have reached pilot or pro duction scale. The main reasons for this slow progress are the complic ated pathways themselves, their complex regulation during the actinomy cete cell cycle, and their uniqueness, as most pathways and products a re specific for a strain rather than for a given species or larger tax onomic group. However, the modular use of a minimum of very similar en zymes and their conversion of similar intermediates to form the buildi ng blocks for the production of a maximum of divergent end products gi ves hope for the future application of these genetic models for the re design of complex pathways for modified or new natural products. Sever al strategies that can be followed to reach this aim are discussed, ma inly for the variable 6-deoxyhexose metabolism as an ubiquitously appl icable example.