Identification of neomacrophorins isolated from Trichoderma sp. 1212-03 as proteasome inhibitors
Identification of neomacrophorins isolated from Trichoderma sp. 1212-03 as proteasome inhibitors
复制标题
从木霉属分离的新巨蛋白的鉴定。
DOI：
10.1016/j.bmc.2019.115161
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发表时间：
2019
影响因子：
3.5
通讯作者：
Kimura K
中科院分区：
文献类型：
--
作者：
Uesugi S;Honmura Y;Nishiyama M;Kusakabe K;Tonouchi A;Yamashita T;Hashimoto M;Kimura K
Neomacrophorins I-III（1-3）和X先前已从木霉sp. 1212-03中分离得到。它们对癌细胞的作用方式和neomacrophorin X特征性[4.4.3]推进剂框架的生物合成机制尚未报道。报道了新巨噬蛋白IV(4)、V(5)和VI(6)的分离和鉴定。环氧醌1、4、6能有效诱导人急性早幼粒细胞白血病HL60细胞凋亡，而环氧半醌2、3、5活性较弱。这表明环氧醌部分对新巨噬蛋白的凋亡诱导活性至关重要。我们还发现新巨噬蛋白在体外抑制蛋白酶体，并且1,4和6诱导HL60细胞中泛素化蛋白的显著积累。这些活性被一种亲核试剂n -乙酰半胱氨酸（NAC）完全抑制。用LC-MS分析反应机理表明，新巨噬蛋白的C2′和C7′可能是与NAC甲酯（ncm）反应的Michael受体。这些发现表明，新巨噬蛋白的亲电特性是其强大的生物效应和新巨噬蛋白X中独特的[4.4.3]推进剂框架的生物合成的原因。
Neomacrophorins I-III (1–3) and X have previously been isolated from Trichoderma sp. 1212-03. Their mode of action against cancer cells and the mechanism of biosynthesis of the characteristic [4.4.3] propellane framework in neomacrophorin X have not been reported. The isolation and characterization of neomacrophorins IV (4), V (5), and VI (6) is reported. Epoxyquinones1,4,and6potently induced apoptotic cell death in human acute promyelocytic leukemia HL60 cells, while epoxysemiquinols2,3,and5showed weak activity. This indicates that the epoxyquinone moiety is crucial for apoptosis-inducing activities of neomacrophorins. We also found that neomacrophorins inhibit proteasomein vitro, and1,4,and6induced significant accumulation of ubiquitinated proteins in HL60 cells. These activities were completely suppressed by a nucleophile,N-acetyl-l-cysteine (NAC). The analysis of reaction mechanisms using LC-MS suggested that C2′ and C7′ of neomacrophorins could be Michael acceptors in the reaction with NAC methyl ester (NACM). These findings indicated that the electrophilic properties of neomacrophorins are responsible for both their potent biological effects and the biosynthesis of unique [4.4.3] propellane framework in neomacrophorin X.