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首页> 外文期刊>Applied Microbiology >Engineered Biosynthesis of Gilvocarcin Analogues with Altered Deoxyhexopyranose Moieties
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Engineered Biosynthesis of Gilvocarcin Analogues with Altered Deoxyhexopyranose Moieties

机译：脱氧己吡喃糖部分改变的吉尔卡霉素类似物的工程生物合成

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A combinatorial biosynthetic approach was used to interrogate the donor substrate flexibility of GilGT, the glycosyltransferase involved in C -glycosylation during gilvocarcin biosynthesis. Complementation of gilvocarcin mutant Streptomyces lividans TK24 (cosG9B3-U~(?)), in which the biosynthesis of the natural sugar donor substrate was compromised, with various deoxysugar plasmids led to the generation of six gilvocarcin analogues with altered saccharide moieties. Characterization of the isolated gilvocarcin derivatives revealed five new compounds, including 4-β- C -d-olivosyl-gilvocarcin V (d-olivosyl GV), 4-β- C -d-olivosyl-gilvocarcin M (d-olivosyl GM), 4-β- C -d-olivosyl-gilvocarcin E (d-olivosyl GE), 4-α- C -l-rhamnosyl-gilvocarcin M (polycarcin M), 4-α- C -l-rhamnosyl-gilvocarcin E (polycarcin E), and the recently characterized 4-α- C -l-rhamnosyl-gilvocarcin V (polycarcin V). Preliminary anticancer assays showed that d-olivosyl-gilvocarcin and polycarcin V exhibit antitumor activities comparable to that of their parent drug congener, gilvocarcin V, against human lung cancer (H460), murine lung cancer (LL/2), and breast cancer (MCF-7) cell lines. Our findings demonstrate GilGT to be a moderately flexible C -glycosyltransferase able to transfer both d- and l-hexopyranose moieties to the unique angucyclinone-derived benzo[d]naphtho[1,2 b ]pyran-6-one backbone of the gilvocarcins.
机译：使用组合的生物合成方法来询问GilGT的供体底物柔性，GilGT是在gilvocarcin生物合成过程中参与C-糖基化的糖基转移酶。 gilvocarcin突变体lividans链霉菌TK24（cosG9B3-U〜（？））的互补物，其中天然糖供体底物的生物合成受到损害，与各种脱氧糖质粒一起导致产生了六个具有改变的糖基的gilvocarcin类似物。分离的gilvocarcin衍生物的表征揭示了五种新化合物，包括4-β-C-d-寡糖基-gilvocarcin V（d-寡糖基GV），4-β-C-d-寡糖基-gilvocarcin M（d-寡糖基GM）， 4-β-C-d-鼠李糖基-Gilvocarcin E（d-寡糖基GE），4-α-C-l-鼠李糖基-Gilvocarcin M（polycarcin M），4-α-C-l-鼠李糖基-gilvocarcin E（polycarcin E），以及最近表征的4-α-C-1-鼠李糖基-gilvocarcin V（polycarcin V）。初步的抗癌试验表明，d-寡糖基-gilvocarcin和polycarcin V的抗肿瘤活性与它们的母体同类药物gilvocarcin V相当，对人肺癌（H460），鼠类肺癌（LL / 2）和乳腺癌（MCF） -7）细胞系。我们的发现表明，GilGT是一种中等柔性的C-糖基转移酶，能够将d-和l-己基吡喃糖部分转移到独特的从环己酮衍生的苯并[d]萘[1,2 b] pyran-6-主链上。

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