earticle

영어

The number of cloned and sequenced genes involved in natural product biosynthesis has increased rapidly during the past decade, and increasing knowledge on genetic information has enabled the manipulation of their biosynthetic pathways to yield novel compounds. However, many of the original producers are difficult to manipulate genetically, have poor growth characteristics, or yield poor titers. The transfer of biosynthetic genes from the original
producers to a more amenable and robust heterologous host therefore becomes an attractive alternative to producing high levels of desired compounds or to providing a basis for subsequent combinatorial biosynthetic approaches. Streptomyces venezuelae has been recently developed as a heterologous host that requires a short culture period for metabolite production compared to other Streptomyces species. It is also amenable to genetic manipulation and has high transformation efficiency. These characteristics make S. venezuelae an alternative system for a rapid heterologous production of desired compounds from benchtop genetic manipulation to product fermentation. For diversifying the structures of microbial natural products or increasing titers, the combinatorial biosynthetic approaches combined with metabolic engineering generated a wide range of unnatural polyketides with increased yield. This approach also enabled us to dissect the biosynthetic pathway of natural products produced by genetically non-amenable bacterial strains such as aminoglycoside-producing actinomycetes. We show here that heterologous expression of different combinations of genes from the 4,6-disubstituted aminoglycoside biosynthetic gene cluster in a non-aminoglycoside producing strain of S. venezuelae caused production of intermediates from the biosynthetic pathway. This provided experimental evidence for assigning the functions of individual gene products and also allowed us to recognize a complete biosynthetic pathway for generation of 4,6-disubstituted aminoglycosides.
References
1. Je Won Park, Jay Sung Joong Hong, Niranjan Parajuli, Won Seok Jung, Sung Ryeol Park, Si-Kyu Lim, Jae Kyung Sohng and Yeo Joon Yoon "Genetic dissection of the biosynthetic route to gentamicin A 2 by heterologous expression of its minimal gene set" (2008) Proceedings of the National Academy of Science of the United States of America 105(24) 8399-8404.