Combinatorial Domain Swaps Provide Insights into the Rules of Fungal Polyketide Synthase Programming and the Rational Synthesis of Non-Native Aromatic Products
Combinatorial Domain Swaps Provide Insights into the Rules of Fungal Polyketide Synthase Programming and the Rational Synthesis of Non-Native Aromatic Products
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DOI：
10.1002/anie.201208550
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Townsend, Craig A.
中科院分区：
文献类型：
--
作者：
Vagstad, Anna L.;Newman, Adam G.;Townsend, Craig A.
聚酮化合物天然产物包含结构和功能多样的分子家族，范围从具有医药重要性的分子到对植物和动物健康产生不利影响的环境毒素。除了以“装配线”方式合成抗生素红霉素大环核心的三重 DEBS 蛋白作为最佳例证的巨型模块化聚酮合酶 (PKS) 之外，[1, 2] 所有其他类别的 PKS 都以迭代方式发挥作用，其中催化结构域的基础集被重复使用固定的或“编程的”次数。脂肪酸合酶 (FAS) 和 PKS 酶类似地使用酰基辅酶 A 前体、作为硫酯的系链中间体，并通过与丙二酰单元的脱羧（硫代）克莱森反应来催化双碳链延伸，但不同之处在于 β-碳加工的程度。一个极端是 FAS，其中起始单元（通常是乙酰基）被延伸，并且在每个 β 羰基处发生逐步还原和脱水，以生成饱和脂肪酸产物。 [3]另一个极端是真菌
Polyketide natural products encompass a structurally and functionally diverse family of molecules ranging from those of pharmaceutical importance to environmental toxins adversely affecting plant and animal health. Apart from the giant, modular polyketide synthases (PKSs) best exemplified by the trio of DEBS proteins that synthesize in an “assembly line” manner the macrocyclic core of the antibiotic erythromycin,[1, 2] all other classes of PKSs function iteratively, in which a basis set of catalytic domains is re-used a fixed, or “programmed”, number of times. Fatty acid synthase (FAS) and PKS enzymes similarly use acyl-CoA precursors, tether intermediates as thioesters, and catalyze twocarbon chain extensions by decarboxylative (thio) Claisen reactions with malonyl units, but differ by the extent of β-carbon processing. At one extreme are the FASs where a starter unit, typically acetyl, is extended and stepwise reductions and dehydration occur at every βcarbonyl to generate saturated fatty acid products.[3] At the other extreme are the fungal