New enzyme functions often evolve through the recruitment and optimization of latent promiscuous activities. How do mutations alter the molecular architecture of enzymes to enhance their activities? Can we infer general mechanisms that are common to most enzymes, or does each enzyme require a unique optimization process? The ability to predict the location and type of mutations necessary to enhance an enzyme's activity is critical to protein engineering and rational design. In this review, via the detailed examination of recent studies that have shed new light on the molecular changes underlying the optimization of enzyme function, we provide a mechanistic perspective of enzyme evolution. We first present a global survey of the prevalence of activity‐enhancing mutations and their distribution within protein structures. We then delve into the molecular solutions that mediate functional optimization, specifically highlighting several common mechanisms that have been observed across multiple examples. As distinct protein sequences encounter different evolutionary bottlenecks, different mechanisms are likely to emerge along evolutionary trajectories toward improved function. Identifying the specific mechanism(s) that need to be improved upon, and tailoring our engineering efforts to each sequence, may considerably improve our chances to succeed in generating highly efficient catalysts in the future.

中文翻译：

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酶进化的机械观点。

新的酶功能通常通过潜在的混杂活动的招募和优化而进化。突变如何改变酶的分子结构以增强其活性？我们能否推断出大多数酶所共有的一般机制，或者每种酶是否都需要独特的优化过程？预测增强酶活性所需的突变位置和类型的能力对于蛋白质工程和合理设计至关重要。在这篇综述中，通过对最近研究的详细检查，这些研究为酶功能优化背后的分子变化提供了新的线索，我们提供了酶进化的机制观点。我们首先对活性增强突变的发生率及其在蛋白质结构中的分布进行了全球调查。然后，我们深入研究介导功能优化的分子解决方案，特别强调在多个示例中观察到的几种常见机制。由于不同的蛋白质序列遇到不同的进化瓶颈，沿着进化轨迹可能会出现不同的机制以改善功能。确定需要改进的具体机制，并根据每个序列调整我们的工程工作，可能会大大提高我们未来成功生产高效催化剂的机会。