Department of Microbiology, Faculty of Agriculture and Forestry, University of Helsinki, Helsinki, Finland.
Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Org Biomol Chem. 2022 Mar 30;20(13):2681-2692. doi: 10.1039/d1ob02454j.
Low-molecular weight natural products display vast structural diversity and have played a key role in the development of novel therapeutics. Here we report the discovery of novel members of the aeruginosin family of natural products, which we named varlaxins. The chemical structures of varlaxins 1046A and 1022A were determined using a combination of mass spectrometry, analysis of one- and two-dimensional NMR spectra, and HPLC analysis of Marfey's derivatives. These analyses revealed that varlaxins 1046A and 1022A are composed of the following moieties: 2--methylglyceric acid 3--sulfate, isoleucine, 2-carboxy-6-hydroxyoctahydroindole (Choi), and a terminal arginine derivative. Varlaxins 1046A and 1022A differ in the cyclization of this arginine moiety. Interestingly, an unusual α-D-glucopyranose moiety derivatized with two 4-hydroxyphenylacetic acid residues was bound to Choi, a structure not previously reported for other members of the aeruginosin family. We sequenced the complete genome of sp. UHCC 0870 and identified the putative 36 kb varlaxin biosynthetic gene cluster. Bioinformatics analysis confirmed that varlaxins belong to the aeruginosin family of natural products. Varlaxins 1046A and 1022A strongly inhibited the three human trypsin isoenzymes with IC of 0.62-3.6 nM and 97-230 nM, respectively, including a prometastatic trypsin-3, which is a therapeutically relevant target in several types of cancer. These results substantially broaden the genetic and chemical diversity of the aeruginosin family and provide evidence that the aeruginosin family is a source of strong inhibitors of human serine proteases.
低分子量天然产物具有广泛的结构多样性，在新型治疗药物的开发中发挥了关键作用。在这里，我们报告了新型天然产物绿蝇菌素家族成员的发现，我们将其命名为 varlaxins。通过质谱分析、一维和二维 NMR 光谱分析以及 Marfey 衍生物的 HPLC 分析，确定了 varlaxin 1046A 和 1022A 的化学结构。这些分析表明，varlaxin 1046A 和 1022A 由以下部分组成：2--甲基甘油酸 3--硫酸盐、异亮氨酸、2-羧基-6-羟基八氢吲哚（Choi）和末端精氨酸衍生物。varlaxin 1046A 和 1022A 在该精氨酸部分的环化方面有所不同。有趣的是，一个不寻常的α-D-吡喃葡萄糖部分与两个 4-羟基苯乙酸残基结合，这一结构以前在绿蝇菌素家族的其他成员中没有报道过。我们测序了 sp. UHCC 0870 的完整基因组，并鉴定了推定的 36 kb varlaxin 生物合成基因簇。生物信息学分析证实 varlaxins 属于绿蝇菌素家族的天然产物。varlaxin 1046A 和 1022A 强烈抑制三种人胰蛋白酶同工酶，IC 为 0.62-3.6 nM 和 97-230 nM，分别为促进转移的胰蛋白酶-3，这是几种癌症的治疗相关靶点。这些结果大大拓宽了绿蝇菌素家族的遗传和化学多样性，并为绿蝇菌素家族是人类丝氨酸蛋白酶强抑制剂的来源提供了证据。
