Functional Trade-Offs in Promiscuous Enzymes Cannot Be Explained by Intrinsic Mutational Robustness of the Native Activity.
Functional Trade-Offs in Promiscuous Enzymes Cannot Be Explained by Intrinsic Mutational Robustness of the Native Activity.
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滥交酶的功能权衡不能用天然活性的内在突变鲁棒性来解释。
DOI：
10.1371/journal.pgen.1006305
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发表时间：
2016-10
期刊：
影响因子：
4.5
通讯作者：
Tokuriki N
中科院分区：
文献类型：
--
作者：
Kaltenbach M;Emond S;Hollfelder F;Tokuriki N
新功能与原有功能的权衡程度是酶进化动力学的一个关键特征。实验室进化的各种案例揭示了一种特征性的趋势：一种新的、混杂的活动的大量增加，往往只伴随着原生的、原始的活动的轻微减少。提出了一个将弱权衡与“进化性”联系起来的模型，认为酶在天然活性中具有突变鲁棒性，在混杂活性中具有可塑性。这将使得能够获得新的功能而不损害原始功能，减少早期基因复制的益处，从而减少其上的选择压力。然而，到目前为止，还没有实验研究直接验证这一假设。在这里，我们调查的原因，弱权衡系统地表征适应性突变发生在两种情况下的进化转变酶的功能：（1）从磷酸三酯酶芳基酯酶，（2）从阿特拉津氯水解酶三聚氰胺脱氨酶。在各种遗传背景的突变分析表明，在流行的模式，相比之下，天然活性是不太强大的突变比混杂的活动。例如，在磷酸三酯酶中，单个突变对天然磷酸三酯酶活性的有害影响远大于它们对混杂芳基酯酶活性的积极影响。我们的观察表明，修订的既定模型：弱权衡不是由固有的鲁棒性的本地活动和可塑性的混杂活动。我们提出，在强大的适应压力，新的活动没有选择对原来的一个，选择的突变将导致最大可能的增加，在新的功能，但是否和在何种程度上减少旧的功能是无关紧要的，创造一个偏向于最初弱的权衡和出现的通才酶。了解酶是如何进化的是一个基本问题，它不仅可以帮助我们在更高水平上破译进化机制，整个生物体，而且还推进了我们的知识序列结构功能关系作为指导人工进化在试管中。在新酶功能的进化过程中发生了一个重要但无法解释的现象;已经观察到新功能和祖先功能通常只是微弱地权衡，这意味着原始的天然活性最初保持在高水平，尽管新的混杂活性有了急剧的改善。先前已经提出，由于天然活性对突变是鲁棒的，而混杂活性则不是，所以发生弱权衡。然而，目前的工作与这一假设相矛盾，基于酶进化的两个例子中突变对这两种活性的影响的详细表征。我们提出了另一种解释：弱活性权衡是一致的，作为一个副产品的强选择的新的活动，而不是一个固有的属性的本地活动。
The extent to which an emerging new function trades off with the original function is a key characteristic of the dynamics of enzyme evolution. Various cases of laboratory evolution have unveiled a characteristic trend; a large increase in a new, promiscuous activity is often accompanied by only a mild reduction of the native, original activity. A model that associates weak trade-offs with “evolvability” was put forward, which proposed that enzymes possess mutational robustness in the native activity and plasticity in promiscuous activities. This would enable the acquisition of a new function without compromising the original one, reducing the benefit of early gene duplication and therefore the selection pressure thereon. Yet, to date, no experimental study has examined this hypothesis directly. Here, we investigate the causes of weak trade-offs by systematically characterizing adaptive mutations that occurred in two cases of evolutionary transitions in enzyme function: (1) from phosphotriesterase to arylesterase, and (2) from atrazine chlorohydrolase to melamine deaminase. Mutational analyses in various genetic backgrounds revealed that, in contrast to the prevailing model, the native activity is less robust to mutations than the promiscuous activity. For example, in phosphotriesterase, the deleterious effect of individual mutations on the native phosphotriesterase activity is much larger than their positive effect on the promiscuous arylesterase activity. Our observations suggest a revision of the established model: weak trade-offs are not caused by an intrinsic robustness of the native activity and plasticity of the promiscuous activity. We propose that upon strong adaptive pressure for the new activity without selection against the original one, selected mutations will lead to the largest possible increases in the new function, but whether and to what extent they decrease the old function is irrelevant, creating a bias towards initially weak trade-offs and the emergence of generalist enzymes. Understanding how enzymes evolve is a fundamental question that can help us decipher not only the mechanisms of evolution on a higher level, i.e., whole organisms, but also advances our knowledge of sequence-structure-function relationships as a guide to artificial evolution in the test tube. An important yet unexplained phenomenon occurs during the evolution of a new enzymatic function; it has been observed that new and ancestral functions often trade-off only weakly, meaning the original native activity is initially maintained at a high level despite drastic improvement of the new promiscuous activity. It has previously been proposed that weak trade-offs occur because the native activity is robust to mutations while the promiscuous activity is not. However, the present work contradicts this hypothesis, based on the detailed characterization of mutational effects on both activities in two examples of enzyme evolution. We propose an alternative explanation: the weak activity trade-off is consistent with being a by-product of strong selection for the new activity rather than an intrinsic property of the native activity.
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DOI：
10.1126/science.1198542
发表时间：
2011-04-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bhabha G;Lee J;Ekiert DC;Gam J;Wilson IA;Dyson HJ;Benkovic SJ;Wright PE
通讯作者：
Wright PE
影响因子：
4.3
作者：
Furnham N;Sillitoe I;Holliday GL;Cuff AL;Laskowski RA;Orengo CA;Thornton JM
通讯作者：
Thornton JM
影响因子：
15
作者：
Devamani T;Rauwerdink AM;Lunzer M;Jones BJ;Mooney JL;Tan MA;Zhang ZJ;Xu JH;Dean AM;Kazlauskas RJ
通讯作者：
Kazlauskas RJ
影响因子：
46.9
作者：
Ghadessy, FJ;Ramsay, N;Holliger, P
通讯作者：
Holliger, P
影响因子：
10.7
作者：
Bank, Claudia;Hietpas, Ryan T.;Bolon, Daniel N. A.
通讯作者：
Bolon, Daniel N. A.