Epoxyquinone Formation Catalyzed by a Two-Component Flavin-Dependent Monooxygenase Involved in Biosynthesis of the Antibiotic Actinorhodin
Epoxyquinone Formation Catalyzed by a Two-Component Flavin-Dependent Monooxygenase Involved in Biosynthesis of the Antibiotic Actinorhodin
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DOI：
10.1002/cbic.201100571
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发表时间：
2011-12-16
期刊：
影响因子：
3.2
通讯作者：
Ichinose, Koji
中科院分区：
文献类型：
--
作者：
Taguchi, Takaaki;Okamoto, Susumu;Ichinose, Koji
天蓝色链霉菌 A3(2) 中芳香族聚酮抗生素放线菌素 (ACT) 的生物合成基因簇携带一对基因 actVA-ORF5 和 actVB，编码双组分黄素依赖性单加氧酶 (FMO)。我们之前的研究表明，ActVA-ORF5/ActVB 系统在 ACT 生物合成中充当醌形成 C-6 加氧酶。此外，我们发现该酶系统与二氢卡拉芬净（DHK）（ACT 生物合成途径中的中间体）表现出额外的氧化活性，并产生两种反应产物。这些化合物被证明是卡拉芬净的单氧衍生物，它是通过 DHK 的氧化内酯化自发形成的。通过 NMR 光谱数据以及计算机建模和 X 射线晶体学阐明了它们的绝对结构为 (5S,14R)-环氧卡拉芬净和 (5R,14S)-环氧卡拉芬净，证明了 ActVA-ORF5/ActVB 系统在体外具有额外的环氧醌形成活性。
The biosynthetic gene cluster of the aromatic polyketide antibiotic actinorhodin (ACT) in Streptomyces coelicolor A3(2) carries a pair of genes, actVA-ORF5 and actVB, that encode a two-component flavin-dependent monooxygenase (FMO). Our previous studies have demonstrated that the ActVA-ORF5/ActVB system functions as a quinone-forming C-6 oxygenase in ACT biosynthesis. Furthermore, we found that this enzyme system exhibits an additional oxygenation activity with dihydrokalafungin (DHK), a proposed intermediate in the ACT biosynthetic pathway, and generates two reaction products. These compounds were revealed to be monooxygenated derivatives of kalafungin, which is spontaneously formed through oxidative lactonization of DHK. Their absolute structures were elucidated from their NMR spectroscopic data and by computer modeling and X-ray crystallography as (5S,14R)-epoxykalafungin and (5R,14S)-epoxykalafungin, demonstrating an additional epoxyquinone-forming activity of the ActVA-ORF5/ActVB system in vitro.