福马克丁血小板激活因子对手的生物合成需要两种酶级联
1State Key Laboratory of Pharmaceutical Biotechnology, Department of Neurology, Nanjing Drum Tower Hospital, School of Life Sciences, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China.
Angewandte Chemie (International ed. in English)
|October 7, 2023
概括
海洋真菌 Phoma sp. 在海洋中生长. 在ATCC 74077中,产生强烈的血小板激活因子 (PAF) 抗剂 - - 福马克丁. 这项研究揭示了这两种复杂的二烯化合物的两种酶生物合成途径 (PhmA和PhmC).
科学领域:
- 自然产品生物合成 自然产品生物合成
- 海洋真菌学 海洋真菌学
- 酶学 是一种酶学.
背景情况:
- 福马克丁二类的特点是复杂的双环[9.3.1]五骨架.
- 这些化合物表现出作为血小板激活因子 (PAF) 抗剂的显著活性,抑制PAF诱导的血小板聚合.
- 了解phomactins的生物合成对于探索它们的治疗潜力至关重要.
研究的目的:
- 在海洋真菌Phoma sp.中识别和描述负责phomactin生物合成的基因集群. 在 ATCC 74077.7.
- 阐明参与麦丁生产的关键酶的酶性机制.
- 为了为合成生物学方法奠定基础,以生产phomactin.
主要方法:
- 在Phoma sp.中的基因集群识别 (phm) 在 ATCC 74077.7.
- 使用I型二烯环酶 (PhmA) 和P450单氧基酶 (PhmC) 的酶分析.
- 同位素标记实验,以调查脚手架的重新安排.
- PhmA的X射线晶体学与基质模拟FGGPP.
- 位点定向的突变发生,以研究酶机制.
主要成果:
- 确定了phm基因集群,编码两个必不可少的酶:PhmA和PhmC.
- PhmA催化形成的前体phomactatriene的形成.
- PhmC进行了连续的氧化,产生了多样化的phomactin结构.
- PhmA的晶体结构揭示了一个新的金属离子结合模式和机制.
- 同位素标记证实了二烯支架重排机制.
结论:
- 复杂的phomactins的生物合成依赖于简化的两个酶系统 (PhmA和PhmC).
- 这项研究提供了第一个全面的洞察力phomactin生物合成.
- 这些发现使未来的合成生物学策略能够有效地生产phomactin.
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