麦克兰:一个前所未有的环氧的结构,生物合成和结合模式,该向20S蛋白质组
Lena Keller1,2, Alberto Plaza1,2, Christian Dubiella3
1†Department of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Pharmaceutical Biotechnology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.
Journal of the American Chemical Society
|June 9, 2015
概括
研究人员发现了macyranone A,这是一种来自myxobacteria的新,它有力地抑制蛋白酶和寄生虫. 这种化合物由于其独特的结构和不可逆转的结合机制,对药物发现有希望.
科学领域:
- 自然产品化学 自然产品化学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 菌根菌是一种独特的生物活性化合物的来源.
- 蛋白质体是各种疾病的关键药物标.
- 需要新的治疗药物来对抗寄生虫感染.
研究的目的:
- 从myxobacterium Cystobacter fuscus MCy9118.8.中分离和描述新的线性.
- 为了阐明这些新的生物合成途径.
- 评估分离化合物的生物活性,特别是它们的蛋白酶抑制和抗寄生虫作用.
主要方法:
- 液体色谱-固相提取-核磁共振质谱 (LC-SPE-NMR-MS) 用于化合物隔离.
- 基因破坏和生物信息分析以确定生物合成基因集群.
- 对酵母和人类蛋白质酶的酶抑制测定 (IC50测定).
- 进行X射线晶体学,以确定macyranone A与蛋白质组的结合方式.
- 在体外对Trypanosoma brucei rhodesiense和Leishmania donovani进行检测.
主要成果:
- 分离了六种线性,macyranones A-F,其中包括一种罕见的2-甲基胺基和一个α-氨基基片段.
- 生物合成基因集群被确定为混合多基酸合成酶/非核糖体合成酶 (PKS/NRPS) 途径.
- 马西兰A证明了酵母 (IC50 = 5.9 nM) 和人类蛋白质体 (IC50 = 21 nM用于构成性,15 nM用于免疫蛋白质体) 的强烈抑制.
- X射线结晶学揭示了macyranoneA不可逆转地与蛋白质酶体的β5亚单元结合,类似于epoxomicin.
- 麦克兰A对Trypanosoma brucei rhodesiense (IC50 = 1.55 μM) 和Leishmania donovani (IC50 = 0.22 μM) 具有显著的活性.
结论:
- 马基兰代表了一种具有独特生物合成途径的新一类天然产品.
- 马西兰A是一种强大的蛋白酶体抑制剂,具有作为治疗的潜力.
- 麦克兰A的结构特征,包括甲基胺胺的残留物,有助于其对蛋白质酶体的强大和特定结合.
- 麦西兰A的抗寄生虫活性需要进一步研究用于治疗被忽视的热带疾病.
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