Gourley D G, Shrive A K, Polikarpov I, Krell T, Coggins J R, Hawkins A R, Isaacs N W, Sawyer L
Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, UK.
Nat Struct Biol. 1999 Jun;6(6):521-5. doi: 10.1038/9287.
The structures of enzymes catalyzing the reactions in central metabolic pathways are generally well conserved as are their catalytic mechanisms. The two types of 3-dehydroquinate dehydratase (DHQase) are therefore most unusual since they are unrelated at the sequence level and they utilize completely different mechanisms to catalyze the same overall reaction. The type I enzymes catalyze a cis-dehydration of 3-dehydroquinate via a covalent imine intermediate, while the type II enzymes catalyze a trans-dehydration via an enolate intermediate. Here we report the three-dimensional structures of a representative member of each type of biosynthetic DHQase. Both enzymes function as part of the shikimate pathway, which is essential in microorganisms and plants for the biosynthesis of aromatic compounds including folate, ubiquinone and the aromatic amino acids. An explanation for the presence of two different enzymes catalyzing the same reaction is presented. The absence of the shikimate pathway in animals makes it an attractive target for antimicrobial agents. The availability of these two structures opens the way for the design of highly specific enzyme inhibitors with potential importance as selective therapeutic agents.
催化中心代谢途径中反应的酶的结构通常高度保守，其催化机制也是如此。因此，两种类型的3-脱氢奎尼酸脱水酶（DHQase）非常特别，因为它们在序列水平上没有关联，并且利用完全不同的机制催化相同的整体反应。I型酶通过共价亚胺中间体催化3-脱氢奎尼酸的顺式脱水，而II型酶通过烯醇中间体催化反式脱水。在此，我们报道了每种类型的生物合成DHQase的一个代表性成员的三维结构。这两种酶都是莽草酸途径的一部分，莽草酸途径在微生物和植物中对于包括叶酸、泛醌和芳香族氨基酸在内的芳香族化合物的生物合成至关重要。本文给出了催化同一反应的两种不同酶存在的一种解释。动物体内缺乏莽草酸途径，这使其成为抗菌剂的一个有吸引力的靶点。这两种结构的可得性为设计具有潜在重要性的高度特异性酶抑制剂开辟了道路，这些抑制剂可作为选择性治疗剂。
