Polyketide-Chain Branching by an Enzymatic Michael Addition
Polyketide-Chain Branching by an Enzymatic Michael Addition
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DOI：
10.1002/anie.200900277
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Hertweck, Christian
中科院分区：
文献类型：
--
作者：
Kusebauch, Bjoern;Busch, Benjamin;Hertweck, Christian
聚酮化合物是一类具有重要生物活性和复杂化学结构的天然产物。[1]无论生产生物体、所涉及的聚酮化合物合酶（PKS）的类型和代谢物的结构如何，聚酮化合物总是通过硫酯与丙二酰基衍生的扩链剂单元的脱羧Claisen型1，2-头-尾缩合形成。[2]然后通过各种剪裁酶进一步加工和修饰所得的线性碳骨架。[3]羰基的α位碳侧链通常衍生自取代的丙二酰基单元或链延长期间或之后的亚甲基烷基化。相比之下，在β位具有一个或两个乙酸酯衍生的碳原子的支链（其对应于前乙酰基羰基（C1））在聚酮化合物中相当稀少。β-烷基化聚酮化合物（其生物合成涉及类异戊二烯样生物合成逻辑）的结构有趣的实例是芽孢杆菌烯（甲基分支）、[4，5]粘病毒素（甲氧基甲基和乙基分支）、[6，7] pederin/onnamide（外亚甲基）、[8-10]苔藓抑素（丙烯酸酯）、[11，12] curacin（环丙基）、[13，14]和牙买加酰胺（氯乙烯）。[15]在迄今为止检查的其中发生β分支事件的所有途径中，采用类似于甲羟戊酸生物合成中的早期步骤的生物合成策略。[16]最近在遗传和生物化学水平的研究表明，酶促CCLIC偶联需要一组酶，包括3-羟基-3-甲基戊二酰辅酶A（HMG）合酶和烯酰辅酶A水合酶（ECH）（或巴豆酸酶）同源物，以及独立的酮合酶（KS）和酰基载体蛋白（ACP）结构域。[16]在这里，我们提出了一种新的生物合成策略的聚酮化合物链的β-分支的直接证据。该转化涉及根霉素途径中的PKS介导的Michael加成。根霉毒素（Rhizoxin，1）是水稻苗枯病病原菌小孢根霉（Rhizopus microsporus）的一种高效抗有丝分裂剂和毒力因子。[17在生物合成研究过程中，我们发现根霉素实际上不是由枯萎病真菌生物合成的，而是由生活在真菌胞质溶胶中的细菌生物合成的。[19-21]通过从内共生体Burkholderia rhizoxinica的基因组中克隆和测序整个根霉素（rhi）生物合成基因簇，我们首次了解了巨大的模块化根霉素装配线。[22日]
The class of polyketides comprises a wealth of natural products, many of which have important biological activities and complex chemical structures.[1] Irrespective of the producing organism, the type of polyketide synthase (PKS) involved, and the structure of the metabolite, polyketides are always formed by decarboxylative Claisen-type 1, 2-head-totail condensations of thioesters with malonyl-derived extender units.[2] The resulting linear carbon backbone is then further processed and modified by various tailoring enzymes.[3] Carbon side chains α to carbonyl groups are typically derived from substituted malonyl units or methylene alkylation during or after chain elongation. In contrast, branches at the β position with one or two acetate-derived carbon atoms, which correspond to former acetyl carbonyl groups (C1), are rather scarce among polyketides. Structurally intriguing examples of β-alkylated polyketides (the biosynthesis of which involves isoprenoid-like biosynthetic logic) are bacillaene (methyl branches),[4, 5] myxovirescin (methoxymethyl and ethyl branches),[6, 7] pederin/onnamide (exomethylene group),[8–10] bryostatin (acrylic ester),[11, 12] curacin (cyclopropyl group),[13, 14] and jamaicamide (vinyl chloride).[15] In all hitherto examined pathways in which a βbranching event takes place, a biosynthetic strategy is employed that resembles early steps in mevalonate biosynthesis.[16] Recent investigations at the genetic and biochemical levels revealed that the enzymatic CÀC coupling requires a set of enzymes that includes 3-hydroxy-3-methylglutaryl-CoA (HMG) synthase and enoyl-CoA hydratase (ECH)(or crotonase) homologues, as well as freestanding ketosynthase (KS) and acyl carrier protein (ACP) domains.[16] Herein we present direct evidence for a novel biosynthetic strategy for the β-branching of a polyketide chain. The transformation involves a PKS-mediated Michael addition in the rhizoxin pathway. Rhizoxin (1) is a highly potent antimitotic agent and virulence factor of the rice-seedlingblight fungus Rhizopus microsporus.[17, 18] In the course of biosynthetic studies, we found that rhizoxin is in fact not biosynthesized by the blight fungus but by bacteria that live within the fungal cytosol.[19–21] Through cloning and sequencing of the entire rhizoxin (rhi) biosynthesis gene cluster from the genome of the endosymbiont Burkholderia rhizoxinica, we gained a first insight into the giant modular rhizoxin assembly line.[22]