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Title

Recombinant strains for the enhanced production of bioengineered rapalogs

AuthorsPetković, Hrvoje ; Wilkinson, Barrie
KeywordsPolyketide
Bioengineering
Rapamycin
Issue Date2013
PublisherElsevier
CitationMetabolic Engineering 15: 167-173 (2013)
AbstractThe rapK gene required for biosynthesis of the DHCHC starter acid that initiates rapamycin biosynthesis was deleted from strain BIOT-3410, a derivative of Streptomyces rapamycinicus which had been subjected to classical strain and process development and capable of robust rapamycin production at titres up to 250 mg/L. The resulting strain BIOT-4010 could no longer produce rapamycin, but when supplied exogenously with DHCHC produced rapamycin at titres equivalent to its parent strain. This strain enabled mutasynthetic access to new rapalogs that could not readily be isolated from lower titre strains when fed DHCHC analogs. Mutasynthesis of some rapalogs resulted predominantly in compounds lacking late post polyketide synthase biosynthetic modifications. To enhance the relative production of fully elaborated rapalogs, genes encoding late-acting biosynthetic pathway enzymes which failed to act efficiently on the novel compounds were expressed ectopically to give strain BIOT-4110. Strains BIOT-4010 and BIOT-4110 represent valuable tools for natural product lead optimization using biosynthetic medicinal chemistry and for the production of rapalogs for pre-clinical and early stage clinical trials
Descriptionet al.
URIhttp://hdl.handle.net/10261/88952
DOIhttp://dx.doi.org/10.1016/j.ymben.2012.11.001
Identifiersdoi: 10.1016/j.ymben.2012.11.001
e-issn: 1096-7184
issn: 1096-7176
Appears in Collections:(IBBTEC) Artículos
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