Alexander Kelsey L, Naman C Benjamin, Iwasaki Arihiro, Mangoni Alfonso, Leao Tiago, Reher Raphael, Petras Daniel, Kim Hyunwoo, Ternon Eva, Caro-Diaz Eduardo J E, Glukhov Evgenia, Mitrevska Jana A, Avalon Nicole E, Duggan Brendan M, Gerwick Lena, Gerwick William H
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California 92093, United States.
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.
J Nat Prod. 2025 Feb 28;88(2):322-335. doi: 10.1021/acs.jnatprod.4c01051. Epub 2025 Jan 29.
A structurally novel metabolite, fatuamide A (), was discovered from a laboratory cultured strain of the marine cyanobacterium sp., collected from Faga'itua Bay, American Samoa. A bioassay-guided approach using NCI-H460 human lung cancer cells directed the isolation of fatuamide A, which was obtained from the most cytotoxic fraction. The planar structure of fatuamide A was elucidated by integrated NMR and MS/MS analysis, and a combination of bioinformatic and computational approaches was used to deduce the absolute configuration at its eight stereocenters. A putative hybrid PKS/NRPS biosynthetic gene cluster responsible for fatuamide A production was identified from the sequenced genomic DNA of the cultured cyanobacterium. The biosynthetic gene cluster possessed elements that suggested fatuamide A binds metals, and this metallophore property was demonstrated by native metabolomics and indicated a preference for binding copper. The producing strain was found to be highly resistant to toxicity from elevated copper concentrations in culture media.
从美国萨摩亚法加伊图阿湾采集的海洋蓝藻菌株的实验室培养物中发现了一种结构新颖的代谢产物，法图酰胺A（）。采用NCI - H460人肺癌细胞的生物活性导向方法指导了法图酰胺A的分离，该产物从细胞毒性最强的部分获得。通过综合核磁共振（NMR）和串联质谱（MS/MS）分析阐明了法图酰胺A的平面结构，并结合生物信息学和计算方法推断其八个立体中心的绝对构型。从培养蓝藻的测序基因组DNA中鉴定出一个负责法图酰胺A生物合成的假定杂交聚酮合酶/非核糖体肽合成酶（PKS/NRPS）生物合成基因簇。该生物合成基因簇具有表明法图酰胺A结合金属的元件，这种金属载体特性通过天然代谢组学得到证实，并表明其对结合铜具有偏好性。发现该生产菌株对培养基中铜浓度升高的毒性具有高度抗性。
