Exploring the Evolution of Novel Enzyme Functions within Structurally Defined Protein Superfamilies

In order to understand the evolution of enzyme reactions and to gain an overview of biological catalysis we have combined sequence and structural data to generate phylogenetic trees in an analysis of 276 structurally defined enzyme superfamilies, and used these to study how enzyme functions have evolved. We describe in detail the analysis of two superfamilies to illustrate different paradigms of enzyme evolution. Gathering together data from all the superfamilies supports and develops the observation that they have all evolved to act on a diverse set of substrates, whilst the evolution of new chemistry is much less common. Despite that, by bringing together so much data, we can provide a comprehensive overview of the most common and rare types of changes in function. Our analysis demonstrates on a larger scale than previously studied, that modifications in overall chemistry still occur, with all possible changes at the primary level of the Enzyme Commission (E.C.) classification observed to a greater or lesser extent. The phylogenetic trees map out the evolutionary route taken within a superfamily, as well as all the possible changes within a superfamily. This has been used to generate a matrix of observed exchanges from one enzyme function to another, revealing the scale and nature of enzyme evolution and that some types of exchanges between and within E.C. classes are more prevalent than others. Surprisingly a large proportion (71%) of all known enzyme functions are performed by this relatively small set of 276 superfamilies. This reinforces the hypothesis that relatively few ancient enzymatic domain superfamilies were progenitors for most of the chemistry required for life.

为解析酶促反应的演化历程并全面认知生物催化机制，本研究整合序列与结构数据，针对276个经结构定义的酶超家族构建系统发育树，并以此探究酶功能的演化规律。我们详细解析了两个超家族的分析过程，用以展示酶演化的不同范式。整合所有超家族的数据集后，我们验证并拓展了此前的观测结论：尽管酶超家族普遍演化出可催化多样底物的功能，但新催化化学反应类型的演化则相对罕见。尽管如此，通过整合如此大规模的数据集，我们仍能够全面概述酶功能变化中最常见与最罕见的类型。本研究在比既往研究更广泛的尺度上证实，整体催化化学反应类型仍存在修饰现象，酶学委员会（Enzyme Commission, E.C.）分类体系一级层级的所有可能功能变化，均在不同程度上被观测到。系统发育树清晰勾勒出单个酶超家族内部的演化路径，以及该超家族内所有可能的功能变化类型。基于此我们构建了酶功能间已知转换的矩阵，该矩阵揭示了酶演化的规模与本质，并发现酶学委员会分类类别间及类内的部分功能转换类型更为普遍。令人意外的是，已知的所有酶功能中，有71%由这仅包含276个超家族的相对小型集合所承担。这一结果进一步佐证了相关假说：生命所需的绝大多数催化化学反应，均起源于数量相对较少的古老酶结构域超家族。