Core Assembly Mechanism of Quinocarcin/SF-1739: Bimodular Complex Nonribosomal Peptide Synthetases for Sequential Mannich-type Reactions
Core Assembly Mechanism of Quinocarcin/SF-1739: Bimodular Complex Nonribosomal Peptide Synthetases for Sequential Mannich-type Reactions
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DOI：
10.1016/j.chembiol.2013.10.011
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发表时间：
2013-12-19
影响因子：
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通讯作者：
Oikawa, Hideaki
中科院分区：
文献类型：
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作者：
Hiratsuka, Tomoshige;Koketsu, Kento;Oikawa, Hideaki
喹诺卡星和SF-1739是两种有效的抗肿瘤抗生素，它们共享一个共同的四环四氢异喹啉(THIQ)-吡咯烷核心支架。在这里，我们描述了他们的生物合成基因簇的鉴定和Qcn18/Cya18产生以前未知的延伸单元脱氢精氨酸的生化分析，脱氢精氨酸是吡咯烷环的一个组成部分。用五种非核糖体肽合成酶(NRPS)进行的ATP-无机焦磷酸交换实验使我们能够确定它们的底物。在这些数据的基础上，我们提出了一个由三个组分的NRPS/MbtH家族蛋白复合体组成的生物合成途径，Qcn16/17/19，在构建四环THIQ-吡咯烷核心支架中发挥了关键作用，包括顺序的Pictet-Spengler反应和分子内Mannich反应。此外，来自基因失活实验的数据使我们提出了奎诺卡星的后期修饰步骤。
Quinocarcin and SF-1739, potent antitumor antibiotics, share a common tetracyclic tetrahydroisoquinoline (THIQ)-pyrrolidine core scaffold. Herein, we describe the identification of their biosynthetic gene clusters and biochemical analysis of Qcn18/ Cya18 generating the previously unidentified extender unit dehydroarginine, which is a component of the pyrrolidine ring. ATP-inorganic pyrophosphate exchange experiments with five nonribosomal peptide synthetases (NRPSs) enabled us to identify their substrates. On the basis of these data, we propose that a biosynthetic pathway comprising a threecomponent NRPS/MbtH family protein complex, Qcn16/17/19, plays a key role in the construction of tetracyclic THIQ-pyrrolidine core scaffold involving sequential Pictet-Spengler and intramolecular Mannich reactions. Furthermore, data derived from gene inactivation experiments led us to propose late-modification steps of quinocarcin.