Abstract
Polyketide antibiotics are among the most important therapeutics used in human and animal health care. Type II polyketides are composed primarily of acetate-derived thioesters, and the subunits for the PKS are contained in a single module that includes a ketosynthase, acyl carrier protein, chain-length factor and sometimes a keto-reductase, aromatase, cyclase and modifying enzymes, such as glycosylases or hydroxylases. While the enzyme complexes that make up the PKS have been the focus of intense study (Khosla in Chem Rev 7:2577–2590, 1997), the pathways for precursor synthesis have not been established and predictions are complicated by the fact that acetate may be derived from a number of metabolic pathways. Here we show that 50% of the acetate for synthesis of the Type II polyketide, actinorhodin, in Streptomyces coelicolor, is derived from the catabolism of the branched amino acids by pathways that are nutrient dependent. The streptomycetes are apparently unique in that they contain two BCDH gene clusters, each of which is potentially capable of converting leucine, valine and isoleucine to the corresponding thioesters, and contain at least three different pathways for valine catabolism that are differentially used in response to nutrient availability.
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Acknowledgments
We thank Kevin Reynolds and Galina Florova for performing the fatty acid analysis and for assistance in interpreting the data, Timothy Dore for his help in interpretation of the fatty acid analysis, Larry Shimketts and Mike Adams for advice throughout the course of the work and for critical review of the manuscript, and David Brown for help in preparation of the figures. K. S. was supported by a predoctoral training grant from the National Institute for General Medical Sciences GM07103 to the Genetics Department of the University of Georgia, an ARCS Foundation Scholarship, as well as a grant from Pfizer, Inc. to J. W.
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Stirrett, K., Denoya, C. & Westpheling, J. Branched-chain amino acid catabolism provides precursors for the Type II polyketide antibiotic, actinorhodin, via pathways that are nutrient dependent. J Ind Microbiol Biotechnol 36, 129–137 (2009). https://doi.org/10.1007/s10295-008-0480-0
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DOI: https://doi.org/10.1007/s10295-008-0480-0