Why nature really chose phosphate.
Why nature really chose phosphate.
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DOI：
10.1017/s0033583512000157
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发表时间：
2013-03
影响因子：
6.1
通讯作者：
Warshel A
中科院分区：
文献类型：
--
作者：
Kamerlin SC;Sharma PK;Prasad RB;Warshel A
磷酸转移在信号传递、能量转导、蛋白质合成和维持遗传物质的完整性等方面起着关键作用。从表面上看，这似乎是一个简单的亲核取代反应。然而，这种简单性是欺骗性的，因为即使在水溶液中，磷原子上的低位d轨道在引入酶催化反应的复杂性之前，也允许八种不同的机理可能性。使问题进一步复杂化的是，虽然强大的传统实验技术，如使用线性自由能关系(LFER)或测量同位素效应，无法在不同的潜在机制之间做出独特的区分。自从韦斯泰默写下他的开创性评论《为什么大自然选择磷酸盐》(科学235(1987)，1173)以来，四分之一个世纪已经过去了，从那时起，这个领域发生了很多变化。本综述重新讨论了这个生物学上的关键问题，探索了相关的酶系统以及水溶液中的相应化学，并表明该领域的关键问题可能得到解决的唯一途径是通过仔细的理论研究(当然，这应该能够重现所有相关的实验数据)。最后，我们证明了大自然真正选择磷酸盐的原因是两种抵消效应之间的相互作用：一方面，磷酸盐是带负电荷的，由此产生的电荷斥力与攻击的亲核试剂有助于很高的水解势，使磷酸酯成为已知的最惰性化合物之一。然而，生物学不仅仅是减少对不利化学反应的障碍。也就是说，同样的电荷斥力使磷酸酯的水解变得如此不利，也使利用静电进行调节成为可能。这意味着，通过微调静电环境，磷酸酯水解不仅可以开启，而且还可以关闭，本综述展示了许多例子。如果没有这种调节能力，就不可能有信号或代谢级联，在这种情况下，每个参与者的行动都是由生产线上前一件产品的微调活动决定的。这使得磷酸酯成为我们所知的促进生活的理想化合物。
Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that nature really chose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.