18 research outputs found

    Functional Characterization of <i>ttnI</i> Completing the Tailoring Steps for Tautomycetin Biosynthesis in <i>Streptomyces griseochromogenes</i>

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    The tautomycetin (TTN) biosynthetic gene cluster has been recently cloned and sequenced from <i>Streptomyces griseochromogenes</i>, unveiling four genes, <i>ttnCDFI</i>, as candidates to encode the tailoring steps for TTN biosynthesis. It is reported that (i) TtnC plays no essential role in TTN biosynthesis, (ii) TtnI catalyzes C-5 oxidation, and (iii) combining the previous findings with TtnFD, the tailoring steps from TTN F-1 to TTN take place in the order of TtnF-catalyzed C-1″/C-2″ dehydration, TtnD-catalyzed C-3″ decarboxylation, and TtnI-catalyzed C-5 oxidation

    Specificity of the Ester Bond Forming Condensation Enzyme SgcC5 in C-1027 Biosynthesis

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    The SgcC5 condensation enzyme catalyzes the attachment of SgcC2-tethered (<i>S</i>)-3-chloro-5-hydroxy-β-tyrosine (<b>2</b>) to the enediyne core in C-1027 (<b>1</b>) biosynthesis. It is reported that SgcC5 (i) exhibits high stereospecificity toward the (<i>S</i>)-enantiomers of SgcC2-tethered β-tyrosine and analogues as donors, (ii) prefers the (<i>R</i>)-enantiomers of 1-phenyl-1,2-ethanediol (<b>3</b>) and analogues, mimicking the enediyne core, as acceptors, and (iii) can recognize a variety of donor and acceptor substrates to catalyze their regio- and stereospecific ester bond formations

    Characterization of Proapoptotic Compounds from the Bark of <i>Garcinia oblongifolia</i>

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    Twenty compounds from <i>Garcinia oblongifolia</i> were screened for proapoptotic activity using FRET-based HeLa-C3 sensor cells. Among them, oblongifolins F and G (<b>1</b> and <b>2</b>), 1,3,5-trihydroxy-13,13-dimethyl-2<i>H</i>-pyran­[7,6-<i>b</i>]­xanthone (<b>3</b>), nigrolineaxanthone T (<b>4</b>), and garcicowin B (<b>5</b>) showed significant proapoptotic activity at a concentration of 10 μM. Bioassessments were then performed to evaluate the potential of these compounds for therapeutic application. All five compounds showed significant cytotoxicity and caspase-3-activating ability in cervical cancer HeLa cells, with compounds <b>1</b> and <b>2</b> having the highest potencies. All five compounds specifically induced caspase-dependent apoptosis, which could be prevented by the pan-caspase inhibitor zVAD-fmk. In particular, <b>3</b> induced apoptosis through mitotic arrest. Compounds <b>1</b>–<b>5</b> displayed similar IC<sub>50</sub> values (3.9–16.5 μM) against the three cancer cell lines HeLa, MDA-MB-435, and HepG2. In addition, compounds <b>1</b>, <b>2</b>, and <b>4</b> exhibited similar and potent IC<sub>50</sub> values (2.4–5.1 μM) against several breast and colon cancer cell lines, including those overexpressing either HER2 or P-glycoprotein. HER2 and P-glycoprotein are known factors that confer resistance to anticancer drugs in cancer cells. This is the first study on the cytotoxicity, caspase-3-activing ability, and specificity of proapoptotic compounds isolated from <i>G. oblongifolia</i> in HeLa cells. The potential application of these compounds against HER2- or P-glycoprotein-overexpressing cancer cells was investigated

    Enediyne Polyketide Synthases Stereoselectively Reduce the β‑Ketoacyl Intermediates to β‑d‑Hydroxyacyl Intermediates in Enediyne Core Biosynthesis

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    PKSE biosynthesizes an enediyne core precursor from decarboxylative condensation of eight malonyl-CoAs. The KR domain of PKSE is responsible for iterative β-ketoreduction in each round of polyketide chain elongation. KRs from selected PKSEs were investigated in vitro with β-ketoacyl-SNACs as substrate mimics. Each of the KRs reduced the β-ketoacyl-SNACs stereoselectively, all affording the corresponding β-d-hydroxyacyl-SNACs, and the catalytic efficiencies (<i>k</i><sub>cat</sub>/<i>K</i><sub>M</sub>) of the KRs increased significantly as the chain length of the β-ketoacyl-SNAC substrate increases

    A new actinomycin Z analogue with an additional oxygen bridge between chromophore and <i>β</i>-depsipentapeptide from <i>Streptomyces</i> sp. KIB-H714

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    <p>Actinomycin Z<sub>6</sub> (<b>1</b>), a new member of the actinomycin family, along with three congeners of the Z-type (Z<sub>1</sub>, Z<sub>3</sub>, Z<sub>5</sub>) actinomycins, are produced from <i>Streptomyces</i> sp. KIB-H714. Their structures were authenticated by comprehensive spectroscopic data interpretation. Different from all the reported Z-type actinomycins, the <i>β</i>-ring of the new compound actinomycin Z<sub>6</sub> includes an additional ring linked between the actinoyl chromophore and <i>β</i>-peptidolactone. In Z<sub>3</sub> and Z<sub>5</sub>, the L-threonine in <i>β</i>-depsipeptide is replaced by the unusual 4-chlorothreonine, an amino acid rarely found in actinomycin family. All isolates were evaluated for cytotoxicity against five human tumor cell lines and for inhibitory activity against <i>Candida albicans</i> and <i>Staphylococcus aureus</i>.</p

    Tropolone Ring Construction in the Biosynthesis of Rubrolone B, a Cationic Tropolone Alkaloid from Endophytic <i>Streptomyces</i>

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    Rubrolones are tropolonoid natural products with a unique carbon skeleton. Extensive secondary metabolite analysis of the endophytic <i>Streptomyces</i> sp. KIB-H033 revealed a new class of rubrolone analogue possessing a rare benzoic acid–pyridine inner salt moiety. Precursor feeding with [<sup>13</sup>C]-acetate revealed a labeling pattern consistent with tropolone moiety construction via type-II PKS chemistry followed by complex oxidative rearrangements. This bacterial biosynthetic route represents a surprising departure from fungal tropolone assembly during stipitatic acid biosynthesis

    Neaumycin: A New Macrolide from <i>Streptomyces</i> sp. NEAU-x211

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    Neaumycin, a new 30-membered macrolide featuring an internal diester bridge, a molecular architecture that is unprecedented among known macrolide natural products, was isolated from a soil actinomycete strain <i>Streptomyces</i> sp. NEAU-x211. The structure of neaumycin was elucidated on the basis of comprehensive mass and NMR spectroscopic interpretation, including the relative stereochemistry of four independent coupling systems

    A new myrsinol-type diterpene polyester from <i>Euphorbia dracunculoides</i> Lam

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    <div><p>A new myrsinol-type diterpene polyester, 14-deoxo-3β-<i>O</i>-propinoyl-2α,5α,7β,15β-tetra-<i>O</i>-acetyl-14α-<i>O</i>-benzoyl-myrsinol (<b>1</b>), and its known analogue, 14-deoxo-3β-<i>O</i>-prorionyl-5α,15β-di-<i>O</i>-acetyl-7β-<i>O</i>-nicotinoyl-myrsinol-14β-acetate (<b>2</b>), together with a monoterpenoid, pubinernoid A (<b>3</b>), two indole alkaloids, neoechinulin A (<b>4</b>) and dihydroxyisoechinulin A (<b>5</b>), two benzene derivatives, siringin (<b>6</b>) and (3-methoxyphenyl) acetic acid (<b>7</b>), were isolated from the 70% acetone extract of the aerial parts of <i>Euphorbia dracunculoides</i> Lam. Their structures were elucidated on the basis of spectroscopic evidence and comparison with literature reports. The absolute configuration of <b>1</b> was deduced by comparing experimental and calculated ECD spectra. Among them, compounds <b>4</b> and <b>5</b> were first obtained from the plant source. In addition, the <sup>13</sup>C NMR data of compound <b>2</b> was reported for the first time.</p></div

    New Duclauxamide from <i>Penicillium manginii</i> YIM PH30375 and Structure Revision of the Duclauxin Family

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    Duclauxamide A1 (<b>1</b>), a new polyketide-derived heptacyclic oligophenalenone dimer with a <i>N</i>-2-hydroxyethyl moiety, was isolated from <i>Penicillium manginii</i> YIM PH30375. Spectroscopic analysis, X-ray single crystal diffraction, and <sup>13</sup>C NMR DFT calculations confirmed that compound <b>1</b> and other duclauxin analogues possess the unified <i>S</i> configuration at C-9′, which corrects a long-standing misrepresentation of duclauxins as C-9′<i>R</i> epimers. A plausible biosynthetic pathway for duclauxins is proposed on the basis of previous acetate labeling results for duclauxin and sclerodin
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