Characterization of JadH as an FAD- and NAD(P)H-Dependent Bifunctional Hydroxylase/Dehydrase in Jadomycin Biosynthesis
Characterization of JadH as an FAD- and NAD(P)H-Dependent Bifunctional Hydroxylase/Dehydrase in Jadomycin Biosynthesis
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DOI：
10.1002/cbic.201000178
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发表时间：
2010-05-17
期刊：
影响因子：
3.2
通讯作者：
Yang, Keqian
中科院分区：
文献类型：
--
作者：
Chen, Yihua;Fan, Keqiang;Yang, Keqian
安古霉素是一类重要的芳香聚酮类天然产物，其结构和生物活性具有显著的多样性。与大多数其他细菌芳香聚酮一样，胍环素是由最小的II型聚酮合成酶组装而成的聚酮链，由酮合成酶α和β异二聚体复合物和同源酰基载体蛋白组成然后通过辅助酶（酮还原酶和环化酶/芳香化酶）修饰聚酮链，生成关键的环素中间体UWM6(1)或其类似物。[2,3]在剪裁酶的催化下，随后的修饰步骤提供了数百种结构多样的安环素大量不同种类的酶参与了安环素的裁剪步骤。对这些酶的研究将有助于我们了解这些分子的生物合成组装机制，这是组合工程生产新型安古霉素所必需的。在所有的裁剪步骤中，C12单氧合作用是值得注意的，因为它发生在所有的安古霉素生物合成途径中，b[4]和对催化该反应的酶的研究将对整个安古霉素家族的生物合成具有重要意义。第一个被表征的催化氨环素C12单氧作用的酶是jadomycin （JD）途径的JadH。JD是指一系列具有独特的五环苯并[b]恶唑噻吩骨架的安古环素分子。[5-7]它们对革兰氏阳性细菌（包括耐甲氧西林金黄色葡萄球菌）具有良好的生物活性最近，jdb （2; Scheme 1）被证明可以抑制Aurora-B激酶的活性jad基因簇于20世纪90年代初从委内瑞拉链霉菌ISP5230中克隆出来，并对其生物合成途径进行了深入分析。[10-12] JadH主要在体内研究中被提出催化C12单氧合和4a， 12b脱水。[13,14]在体外也被证明可以将2,3 -脱氢- uwm6(3)转化为脱氢拉贝霉素(4)，将1转化为拉贝霉素(5)（方案2）研究
As a major class of aromatic polyketide natural products, the angucyclines display significant diversity in structure and bioactivity. Like most other bacterial aromatic polyketides, angucyclines are derived from polyketide chains assembled by the minimal type II polyketide synthases, which consist of a ketosynthase α and β heterodimer complex and a cognate acyl carrier protein.[1] The polyketide chains are then modified by accessory enzymes (ketoreductase and cyclase/aromatase) to generate the key angucycline intermediates, UWM6 (1) or its analogues.[2, 3] Subsequent modification steps catalyzed by tailoring enzymes afford the hundreds of structurally diverse angucyclines that have been identified.[4] A large number of different kinds of enzymes are involved in the tailoring steps of angucyclines. Investigation of these enzymes will help us to understand the mechanism of biosynthetic assembly of these molecules, and this knowledge is required for combinatorial engineering to produce novel angucyclines. Among all the tailoring steps, C12 monooxygenation is remarkable in that it takes place in all angucycline biosynthetic pathways,[4] and investigation of the enzyme catalyzing this reaction should shed significant light on the biosyntheses of the whole angucycline family.The first characterized enzyme catalyzing angucycline C12 monooxygenation is JadH from jadomycin (JD) pathway. JD refers to a series of angucycline molecules with a unique pentacyclic benz [b] oxazolophenanthridine skeleton.[5–7] They exhibit good bioactivity against Gram-positive bacteria, including the methicillin-resistant Staphylococcus aureus.[8] Recently, JD B (2; Scheme 1) was shown to inhibit the activity of Aurora-B kinase.[9] The jad gene cluster was cloned from Streptomyces venezuelae ISP5230 in the early 1990s, and the JD biosynthetic pathway has been thoroughly analyzed.[10–12] JadH was proposed to catalyze the C12 monooxygenation and 4a, 12b-dehydration from mainly in vivo investigations.[13, 14] It was also shown to convert 2, 3-dehydro-UWM6 (3) to dehydrorabelomycin (4) and 1 to rabelomycin (5) in vitro (Scheme 2).[13] Studies