Insight into a natural Diels-Alder reaction from the structure of macrophomate synthase
Insight into a natural Diels-Alder reaction from the structure of macrophomate synthase
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DOI：
10.1038/nature01454
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发表时间：
2003-03-13
期刊：
影响因子：
64.8
通讯作者：
Tanaka, I
中科院分区：
文献类型：
--
作者：
Ose, T;Watanabe, K;Tanaka, I
Diels-Alder反应由烯烃（亲二烯体）和1，3-二烯形成六元环，在温和条件下合成具有高区域和立体选择性的环状产物非常有用（1）。它已被应用于合成复杂的药物和生物活性化合物（2）。尽管在次级代谢物的生物合成中积累了关于天然狄尔斯-阿尔德酶的证据（3-7）（8），但还没有关于天然狄尔斯-阿尔德酶的结构细节的报道。由于天然Diels-Alder加合物中分子骨架的多样性，天然Diels-Alder酶的功能和催化机制引起了极大的兴趣（8）。在这里，我们展示了与丙酮酸复合的天然狄尔斯-阿尔德酶，真菌巨噬细胞酸合酶（MPS）（3）的1.70埃分辨率晶体结构。该酶的活性位点是大的和疏水性的，有助于氨基酸残基，可以氢键底物2-吡喃酮。这些数据提供了有关MPS催化机制的信息，并表明反应通过产物的大规模结构重组进行。
The Diels-Alder reaction, which forms a six-membered ring from an alkene (dienophile) and a 1,3-diene, is synthetically very useful for construction of cyclic products with high regio- and stereoselectivity under mild conditions(1). It has been applied to the synthesis of complex pharmaceutical and biologically active compounds(2). Although evidence(3-7) on natural Diels-Alderases has been accumulated in the biosynthesis of secondary metabolites(8), there has been no report on the structural details of the natural Diels-Alderases. The function and catalytic mechanism of the natural Diels-Alderase are of great interest owing to the diversity of molecular skeletons in natural Diels-Alder adducts(8). Here we present the 1.70 Angstrom resolution crystal structure of the natural Diels-Alderase, fungal macrophomate synthase (MPS)(3), in complex with pyruvate. The active site of the enzyme is large and hydrophobic, contributing amino acid residues that can hydrogen-bond to the substrate 2-pyrone. These data provide information on the catalytic mechanism of MPS, and suggest that the reaction proceeds via a large-scale structural reorganization of the product.