Baier Florian, Tokuriki Nobuhiko
Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
J Mol Biol. 2014 Jun 26;426(13):2442-56. doi: 10.1016/j.jmb.2014.04.013. Epub 2014 Apr 24.
The expansion of functions in an enzyme superfamily is thought to occur through recruitment of latent promiscuous functions within existing enzymes. Thus, the promiscuous activities of enzymes represent connections between different catalytic landscapes and provide an additional layer of evolutionary connectivity between functional families alongside their sequence and structural relationships. Functional connectivity has been observed between individual functional families; however, little is known about how catalytic landscapes are connected throughout a highly diverged superfamily. Here, we describe a superfamily-wide analysis of evolutionary and functional connectivity in the metallo-β-lactamase (MBL) superfamily. We investigated evolutionary connections between functional families and related evolutionary to functional connectivity; 24 enzymes from 15 distinct functional families were challenged against 10 catalytically distinct reactions. We revealed that enzymes of this superfamily are generally promiscuous, as each enzyme catalyzes on average 1.5 reactions in addition to its native one. Catalytic landscapes in the MBL superfamily overlap substantially; each reaction is connected on average to 3.7 other reactions whereas some connections appear to be unrelated to recent evolutionary events and occur between chemically distinct reactions. These findings support the idea that the highly distinct reactions in the MBL superfamily could have evolved from a common ancestor traversing a continuous network via promiscuous enzymes. Several functional connections (e.g., the lactonase/phosphotriesterase and phosphonatase/phosphodiesterase/arylsulfatase reactions) are also observed in structurally and evolutionary distinct superfamilies, suggesting that these catalytic landscapes are substantially connected. Our results show that new enzymatic functions could evolve rapidly from the current diversity of enzymes and range of promiscuous activities.
酶超家族中功能的扩展被认为是通过募集现有酶中潜在的混杂功能而发生的。因此，酶的混杂活性代表了不同催化格局之间的联系，并在功能家族之间除了其序列和结构关系之外提供了额外一层进化连通性。在各个功能家族之间已经观察到功能连通性；然而，对于在一个高度分化的超家族中催化格局是如何相互连接的却知之甚少。在这里，我们描述了对金属β-内酰胺酶（MBL）超家族中进化和功能连通性的全超家族分析。我们研究了功能家族之间的进化联系以及与功能连通性相关的进化；来自15个不同功能家族的24种酶被用于测试10种催化不同的反应。我们发现这个超家族的酶通常具有混杂性，因为每种酶除了其天然催化的反应外平均还能催化1.5种反应。MBL超家族中的催化格局有很大程度的重叠；每个反应平均与3.7个其他反应相连，而一些联系似乎与最近的进化事件无关，并且发生在化学性质不同的反应之间。这些发现支持了这样一种观点，即MBL超家族中高度不同的反应可能是从一个共同祖先通过混杂酶穿越一个连续网络进化而来的。在结构和进化上不同的超家族中也观察到了一些功能联系（例如，内酯酶/磷酸三酯酶和磷酸酶/磷酸二酯酶/芳基硫酸酯酶反应），这表明这些催化格局有很大的关联性。我们的结果表明，新的酶功能可以从当前酶的多样性和混杂活性范围中迅速进化出来。
