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Designed divergent evolution of enzyme function.

机译：设计的酶功能发散进化。

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It is generally believed that proteins with promiscuous functions divergently evolved to acquire higher specificity and activity, and that this process was highly dependent on the ability of proteins to alter their functions with a small number of amino acid substitutions (plasticity). The application of this theory of divergent molecular evolution to promiscuous enzymes may allow us to design enzymes with more specificity and higher activity. Many structural and biochemical analyses have identified the active or binding site residues important for functional plasticity (plasticity residues). To understand how these residues contribute to molecular evolution, and thereby formulate a design methodology, plasticity residues were probed in the active site of the promiscuous sesquiterpene synthase gamma-humulene synthase. Identified plasticity residues were systematically recombined based on a mathematical model in order to construct novel terpene synthases, each catalysing the synthesis of one or a few very different sesquiterpenes. Here we present the construction of seven specific and active synthases that use different reaction pathways to produce the specific and very different products. Creation of these enzymes demonstrates the feasibility of exploiting the underlying evolvability of this scaffold, and provides evidence that rational approaches based on these ideas are useful for enzyme design.
机译：一般认为，具有混杂功能的蛋白质会发散地进化以获得更高的特异性和活性，并且该过程高度依赖于蛋白质利用少量氨基酸取代（可塑性）改变其功能的能力。这种发散性分子进化理论在混杂酶中的应用可能使我们能够设计具有更高特异性和更高活性的酶。许多结构和生化分析已经确定了对功能可塑性重要的活性或结合位点残基（可塑性残基）。为了了解这些残基如何促进分子进化，从而制定了一种设计方法，在混杂倍半萜烯合酶γ-腐植烯合酶的活性位点探测了可塑性残基。基于数学模型，系统地将识别出的可塑性残基进行重组，以构建新型的萜烯合酶，每种酶催化一种或几种非常不同的倍半萜烯的合成。在这里，我们介绍了七个特异性和活性合酶的构建，它们使用不同的反应途径来产生特异性和非常不同的产物。这些酶的产生证明了利用该支架的潜在进化能力的可行性，并提供了证据表明基于这些思想的合理方法可用于酶设计。

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