Abstract
The structural repertoire of bioactive naphthacene quinones is expanded by engineering Streptomyces albus to express the lysolipin minimal polyketide synthase II (PKS II) genes from Streptomyces tendae Tü 4042 (llpD-F) with the corresponding cyclase genes llpCI-CIII. Fermentation of the recombinant strain revealed the two new polyaromatic tridecaketides lysoquinone-TH1 (7, identified) and TH2 (8, postulated structure) as engineered congeners of the dodecaketide lysolipin (1). The chemical structure of 7, a benzo[a]naphthacene-8,13-dione, was elucidated by NMR and HR-MS and confirmed by feeding experiments with [1,2-13C2]-labeled acetate. Lysoquinone-TH1 (7) is a pentangular polyphenol and one example of such rare extended polyaromatic systems of the benz[a]napthacene quinone type produced by the expression of a minimal PKS II in combination with cyclases in an artificial system. While the natural product lysolipin (1) has antimicrobial activity in nM-range, lysoquinone-TH1 (7) showed only minor potency as inhibitor of Gram-positive microorganisms. The bioactivity profiling of lysoquinone-TH1 (7) revealed inhibitory activity towards phosphodiesterase 4 (PDE4), an important target for the treatment in human health like asthma or chronic obstructive pulmonary disease (COPD). These results underline the availability of pentangular polyphenolic structural skeletons from biosynthetic engineering in the search of new chemical entities in drug discovery.
Highlights
Polyketides are a large family of structurally-diverse natural products, mainly produced by bacteria, fungi, and plants
The genes of the lysolipin minimal polyketide synthase II (PKS II), which are surrounded by the cyclases llpCI, llpCII, and llpCIII, were amplified by PCR using the primers minPKScyc-fw-Hind and minPKScyc-revSs and the template cosmid 4H04 [21] using ProofStart PCR polymerase kit (Qiagen)
Lysoquinone-TH1 (7) is a “non-natural natural product”, a pentangular aromatic polyketide derived from engineering of the lysolipin biosynthetic pathway
Summary
Polyketides are a large family of structurally-diverse natural products, mainly produced by bacteria, fungi, and plants. Their biosynthesis is catalyzed by distinct enzymes, termed type I polyketide synthases (PKS), type II PKS, type III PKS or variants thereof [1]. They exhibit broad ranges of pharmacological properties for use in clinical applications [2]. PKS contains a minimal set of enzymes by type II polyketide synthases (PKS II). Each PKS II contains a minimal set of enzymes (minPKS)
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