Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, 6-3 Aramaki-Aza-Aoba, Aoba-ku, Sendai, Miyagi, Japan.
Graduate School of Agricultural Science, Tohoku University 468-1 Aramaki-Aza-Aoba, Aoba-ku, Sendai, Miyagi, Japan.
Biosci Biotechnol Biochem. 2022 Sep 23;86(10):1333-1342. doi: 10.1093/bbb/zbac131.
Natural products containing the highly unusual phosphotriester ring are known to be potent serine hydrolase inhibitors. The long-chain bicyclic enol-phosphotriester salinipostins (SPTs) from the marine actinomycete Salinispora have been identified as selective antimalarial agents. A potential regulatory function has been suggested for phosphotriesters based on their structural relationship with actinomycete signaling molecules and the prevalence of spt-like biosynthetic gene clusters across actinomycetes. In this study, we established a mass spectrometry-guided screening method for phosphotriesters focusing on their characteristic fragment ions. Applying this screening method to the SPT producer Salinispora tropica CNB-440, new SPT analogs (4-6) were discovered and their structures were elucidated by spectroscopic analyses. Previously known and herein-identified SPT analogs inhibited the activity of human monoacylglycerol lipase (MAGL), a key serine hydrolase in the endocannabinoid system, in the nanomolar range. Our method could be applied to the screening of phosphotriesters, potential serine hydrolase inhibitors and signaling molecules.
天然产物中含有高度不寻常的膦酸三酯环，已知是强效丝氨酸水解酶抑制剂。海洋放线菌盐单胞菌中的长链双环烯醇膦酸三酯盐（SPT）已被鉴定为选择性抗疟药物。基于它们与放线菌信号分子的结构关系以及 spt 样生物合成基因簇在放线菌中的普遍性，有人提出了磷酸三酯酶的潜在调节功能。在这项研究中，我们建立了一种基于特征碎片离子的质谱引导的磷酸三酯酶筛选方法。将该筛选方法应用于 SPT 产生菌盐单胞菌 tropica CNB-440，发现了新的 SPT 类似物（4-6），并通过光谱分析阐明了它们的结构。以前已知和在此鉴定的 SPT 类似物以纳摩尔范围抑制人单酰基甘油脂肪酶（MAGL）的活性，MAGL 是内源性大麻素系统中的关键丝氨酸水解酶。我们的方法可应用于磷酸三酯酶、潜在的丝氨酸水解酶抑制剂和信号分子的筛选。
