Genetic engineering and heterologous expression of the disorazol biosynthetic gene cluster via Red/ET recombineering.
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Authors
Tu, QiangHerrmann, Jennifer
Hu, Shengbiao
Raju, Ritesh
Bian, Xiaoying
Zhang, Youming
Müller, Rolf

Issue Date
2016
Metadata
Show full item recordAbstract
Disorazol, a macrocyclic polykitide produced by the myxobacterium Sorangium cellulosum So ce12 and it is reported to have potential cytotoxic activity towards several cancer cell lines, including multi-drug resistant cells. The disorazol biosynthetic gene cluster (dis) from Sorangium cellulosum (So ce12) was identified by transposon mutagenesis and cloned in a bacterial artificial chromosome (BAC) library. The 58-kb dis core gene cluster was reconstituted from BACs via Red/ET recombineering and expressed in Myxococcus xanthus DK1622. For the first time ever, a myxobacterial trans-AT polyketide synthase has been expressed heterologously in this study. Expression in M. xanthus allowed us to optimize the yield of several biosynthetic products using promoter engineering. The insertion of an artificial synthetic promoter upstream of the disD gene encoding a discrete acyl transferase (AT), together with an oxidoreductase (Or), resulted in 7-fold increase in disorazol production. The successful reconstitution and expression of the genetic sequences encoding for these promising cytotoxic compounds will allow combinatorial biosynthesis to generate novel disorazol derivatives for further bioactivity evaluation.Citation
Genetic engineering and heterologous expression of the disorazol biosynthetic gene cluster via Red/ET recombineering. 2016, 6:21066 Sci RepAffiliation
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS),Saarland 9 University, 66123 Saarbrücken, Germany.Journal
Scientific reportsPubMed ID
26875499Type
ArticleLanguage
enISSN
2045-2322ae974a485f413a2113503eed53cd6c53
10.1038/srep21066
Scopus Count
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