Coupling Reaction of Indolepyruvic Acid by StaD and Its Product: Implications for Biosynthesis of Indolocarbazole and Violacein
Coupling Reaction of Indolepyruvic Acid by StaD and Its Product: Implications for Biosynthesis of Indolocarbazole and Violacein
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DOI：
10.1002/cbic.201200535
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发表时间：
2012-11-26
期刊：
影响因子：
3.2
通讯作者：
Nagano, Shingo
中科院分区：
文献类型：
--
作者：
Asamizu, Shumpei;Hirano, Satoshi;Nagano, Shingo
吲哚咔唑天然产物具有多种形式的生物活性。Rebeccamycin是一种分离自航空结肠Lechevalieria的产物，是DNA拓扑异构酶I的抑制剂，而staurosporine是从几种链霉菌中分离出来的，是一种有效的蛋白激酶ec抑制剂。这些化合物是很有前途的抗肿瘤候选药物，一些衍生物目前正在临床试验中。[1,2]吲哚咔唑苷元是一种高度共轭的平面六环融合发色团，通常主要由四种氧化酶产生。[3,4]在星孢素的生物合成中，色氨酸被StaO酶氧化生成吲哚丙酮酸亚胺（IPA亚胺；Scheme1）。有人提出，含有血红素的酶StaD在每个C-8原子上偶联两个IPA亚胺分子，产生中间的IPA亚胺二聚体，该二聚体自发转化为铬吡咯酸[5](CPA，也称为糖没食子酸[6])，正如Paal-Knorr合成中所观察到的那样。[7,8]细胞色素P450 StaP和含黄素单加氧酶StaC先后将CPA氧化为staurosporine glycone （K252c）。[9-11]其他几个吲哚咔唑生物合成基因簇已经被报道，并且类似于在staurosporine生物合成系统中发现的酶参与苷元的形成。[12-17]在吲哚咔唑和紫罗兰素的生物合成途径中，IPA亚胺的偶联是至关重要的，因为该反应处于两个途径的分支点，其产物是共同的前体对StaD和RebD （StaD的一种同系物）的生化研究表明，这两种酶都利用IPA
Indolocarbazole natural products display various forms of bioactivity. Rebeccamycin, a product isolated from Lechevalieria aerocolonigenes, is an inhibitor of DNA topoisomerase I, whereas staurosporine, which is isolated from several Streptomyces species, is a potent protein kinaseC inhibitor. These compounds are promising antitumor drug candidates, and several derivatives are currently in clinical trials.[1, 2] Indolocarbazole aglycone is a highly conjugated planar sixring-fused chromophore usually produced primarily by four oxidative enzymes.[3, 4] In staurosporine biosynthesis, tryptophan is oxidized by the enzyme StaO to produce the imine of indolepyruvic acid (IPA imine; Scheme1). It has been proposed that a heme-containing enzyme, StaD, couples two molecules of IPA imine at each C-8 atom, producing an intermediate IPA imine dimer, which is spontaneously converted into chromopyrrolic acid [5](CPA, also known as lycogalic acid [6]), as is observed in the Paal–Knorr synthesis.[7, 8] Cytochrome P450 StaP and the flavin-containing monooxygenase StaC successively oxidize CPA to staurosporine aglycone (K252c).[9–11] Several other indolocarbazole biosynthetic gene clusters have been reported, and enzymes similar to those found in the staurosporine biosynthesis system are involved in aglycone formation.[12–17]In the indolocarbazole and violacein biosynthetic pathways, the coupling of the IPA imine is critical because the reaction is at the branch point of two pathways and its product is a common precursor.[18] Biochemical studies of StaD and RebD (a StaD homologue) indicate that the enzymes use the IPA